JP2724396B2 - Osteoporosis prevention and treatment agent - Google Patents
Osteoporosis prevention and treatment agentInfo
- Publication number
- JP2724396B2 JP2724396B2 JP63318750A JP31875088A JP2724396B2 JP 2724396 B2 JP2724396 B2 JP 2724396B2 JP 63318750 A JP63318750 A JP 63318750A JP 31875088 A JP31875088 A JP 31875088A JP 2724396 B2 JP2724396 B2 JP 2724396B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- optionally substituted
- naphthyridyl
- alkoxy
- pyridyl
- 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 - Lifetime
Links
- 208000001132 Osteoporosis Diseases 0.000 title claims description 8
- 230000002265 prevention Effects 0.000 title description 2
- -1 pyrido [2,3-d] pyrimidyl Chemical group 0.000 claims description 130
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000004306 triazinyl group Chemical group 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- 125000004442 acylamino group Chemical group 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 230000003449 preventive effect Effects 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 150000002513 isocyanates Chemical class 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 210000000988 bone and bone Anatomy 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
- 125000000547 substituted alkyl group Chemical group 0.000 description 7
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 6
- 208000006386 Bone Resorption Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000024279 bone resorption Effects 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000012948 isocyanate Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 150000007945 N-acyl ureas Chemical class 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- 150000008349 1,2,4-benzothiadiazines Chemical class 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000005017 substituted alkenyl group Chemical group 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 1
- ZGYVGZHSMYBSDV-UHFFFAOYSA-N 1-tert-butyl-3-(2-methylphenyl)urea Chemical compound CC1=CC=CC=C1NC(=O)NC(C)(C)C ZGYVGZHSMYBSDV-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
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- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000000623 ulna Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、1,2,4−ベンゾチアジアジン誘導体を含有
してなる骨粗鬆症予防治療剤に関する。Description: TECHNICAL FIELD The present invention relates to an agent for preventing and treating osteoporosis comprising a 1,2,4-benzothiadiazine derivative.
従来の技術 骨粗鬆症は、骨の量的減少がある程度以上になって、
そのために何らかの症状または危険を起こしている病的
状態あるいは疾患である。その主要症状は脊椎の後彎，
腰背骨ならびに椎体，大腿骨頚部，橈骨下端，肋骨，上
腕骨上端等の骨折である。その原因は内分泌および栄養
障害等多様である。従来、治療薬としてはエストロゲン
剤，カルシトニン，ビタミンＤおよびカルシウム剤等が
投与されている。2. Description of the Related Art Osteoporosis is a phenomenon in which the amount of bone loss exceeds a certain level.
A pathological condition or disease that is causing some symptoms or dangers. The main symptoms are kyphosis of the spine,
It is a fracture of the lumbar spine, vertebral body, femoral neck, lower radius, ribs, upper humerus, etc. The causes are diverse, including endocrine and malnutrition. Conventionally, estrogen agents, calcitonin, vitamin D, calcium agents, and the like have been administered as therapeutic agents.
発明が解決しようとする問題点 しかしながら、上記の治療薬を投与する場合、投与対
象が限定されたり、効果が不確実である場合もあり十分
な効果が得られていない。Problems to be Solved by the Invention However, when the above-mentioned therapeutic agents are administered, the administration targets are limited, and the effects may be uncertain, and sufficient effects have not been obtained.
問題点を解決するための手段 そこで本発明者らは、骨に直接作用して骨吸収を抑制
する、より一般的な薬剤の開発を目的として鋭意研究を
行なった結果、下記一般式（Ｉ）で表わされる1,2,4−
ベンゾチアジアジン誘導体が骨に直接作用してすぐれた
骨吸収抑制作用を示すことを見出し、本発明を完成し
た。Means for Solving the Problems Accordingly, the present inventors have conducted intensive studies with the aim of developing a more general drug that acts directly on bone to suppress bone resorption, and as a result, the following general formula (I) 1,2,4-
The present inventors have found that a benzothiadiazine derivative acts directly on bone and exhibits an excellent bone resorption inhibiting action, and thus completed the present invention.
すなわち本発明は、 一般式（Ｉ） ［式中、R1およびR2は同一または異なって水素，ハロゲ
ン原子，置換されていてもよい低級アルキル，置換され
ていてもよい水酸基，または低級アシルを示すか、ある
いは隣接するR1とR2とが互いに連結して式CH2 m［式
中、ｍは３〜５の整数を示す］または式−ＯCH2 nＯ
−［式中、ｎは１〜３の整数を示す］で表わされる環を
形成することを示し、R3は水素，低級アルキルあるいは
アラルキルを、R4は水素またはそれぞれ置換されていて
もよいアルキル，アラルキル，アルケニル，芳香族ある
いは複素環基を示す。］で表わされる化合物またはその
塩を含有してなる骨粗鬆症予防治療剤および一般式 ［式中、R1およびR2は同一または異なって水素，ハロゲ
ン原子，置換されていてもよい低級アルキル，置換され
ていてもよい水酸基，または低級アシルを示すか、ある
いは隣接するR1とR2とが互いに連結して式−（CH2）ｍ
−（式中、ｍは３〜５の整数を示す）または式−Ｏ−
（CH2）ｎ−Ｏ−（式中、ｎは１〜３の整数を示す）で
表される環を形成することを示し、R3は水素，低級アル
キルあるいはアラルキルを、R4″はメチル，エチルまた
はベンジルを示す。ただし、R1，R2およびR3は同時に水
素ではない］で表される化合物またはその塩に関する。That is, the present invention provides a compound represented by the general formula (I): [Wherein, R 1 and R 2 are the same or different and each represent hydrogen, a halogen atom, an optionally substituted lower alkyl, an optionally substituted hydroxyl group, or a lower acyl, or two adjacent R 1 and R 2 formula CH 2 m [wherein, m represents an integer of 3-5] and 2 are connected to each other or the formula -OCH 2 n O
-Represents a ring represented by the formula: wherein n represents an integer of 1 to 3, R 3 represents hydrogen, lower alkyl or aralkyl, and R 4 represents hydrogen or optionally substituted alkyl , Aralkyl, alkenyl, aromatic or heterocyclic groups. And an agent for preventing or treating osteoporosis comprising the compound represented by the formula: [Wherein, R 1 and R 2 are the same or different and each represent hydrogen, a halogen atom, an optionally substituted lower alkyl, an optionally substituted hydroxyl group, or a lower acyl, or two adjacent R 1 and R 2 And 2 are linked to each other to form the formula-(CH 2 ) m
-(Wherein, m represents an integer of 3 to 5) or -O-
(CH 2 ) n—O— (wherein n represents an integer of 1 to 3), R 3 represents hydrogen, lower alkyl or aralkyl, and R 4 ″ represents methyl , Ethyl or benzyl, provided that R 1 , R 2 and R 3 are not simultaneously hydrogen.] Or a salt thereof.
前記式（Ｉ）中、R1またはR2で示されるハロゲンの例
としてはフッ素，塩素，臭素およびヨウ素があげられ、
とりわけ塩素が好ましい。In the formula (I), examples of the halogen represented by R 1 or R 2 include fluorine, chlorine, bromine and iodine;
Particularly, chlorine is preferred.
R1またはR2で示される置換されていてもよい低級アル
キルにおける低級アルキルとしては炭素数１〜６のもの
が好ましく、たとえばメチル，エチル，プロピル，イソ
プロピル，ブチル，イソブチル,sec−ブチル,tert−ブ
チル，ペンチル，イソペンチル，ネオペンチル，ヘキシ
ルなどがあげられる。The lower alkyl in the optionally substituted lower alkyl represented by R 1 or R 2 is preferably a lower alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
R1またはR2で示される置換されていてもよい水酸基と
しては、水酸基およびこの水酸基に適宜の置換基、特に
水酸基の保護基として用いられるものを有した、たとえ
ばアルコキシ，アラルキルオキシ，アシルオキシなどが
あげられる。該アルコキシとしては，炭素数が１〜６の
低級アルコキシ（例、メトキシ，エトキシ，プロポキ
シ，イソプロポキシ，ブトキシ，イソブトキシ,sec−ブ
トキシ,tert−ブトキシ，ペントキシ，イソペントキ
シ，ネオペントキシ，ヘキシルオキシなど）が好まし
い。該アラルキルオキシとしては、たとえばフェニル−
C1-4アルキルオキシ（例、ベンジルオキシ，フェネチル
オキシなど）があげられる。該アシルオキシとしては、
炭素数が２〜４のアルカノイルオキシ（例、アセチルオ
キシ，プロピオニルオキシ,n−ブチリルオキシ,iso−ブ
チリルオキシなど）が好ましい。Examples of the optionally substituted hydroxyl group represented by R 1 or R 2 include a hydroxyl group and an appropriate substituent on this hydroxyl group, particularly those having a substituent used as a protecting group for the hydroxyl group, for example, alkoxy, aralkyloxy, acyloxy and the like. can give. The alkoxy is preferably a lower alkoxy having 1 to 6 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, etc.). . As the aralkyloxy, for example, phenyl-
C 1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). As the acyloxy,
Alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy, etc.) is preferred.
R1またはR2で示される低級アシルとしては、ホルミル
または前記R1，R2について記した炭素数１〜６のアルキ
ルとカルボニル基の結合したもの（例、アセチル，プロ
ピオニル，ブチリル，イソブチリル，バレリル，イソバ
レリル，ピバロイル等）があげられる。Examples of the lower acyl represented by R 1 or R 2 include formyl or a combination of the alkyl having 1 to 6 carbon atoms described for R 1 and R 2 and a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl) , Isovaleryl, pivaloyl, etc.).
R1とR2とが互いに隣接しているときは、R1とR2とが連
結してCH2 mまたは−ＯCH2 nＯ−で示される環を
形成していてもよく、かかる環はベンゼン環の炭素原子
とともに形成される５〜７員環を含む。これら環の中で
はｍが３または４の５〜６員環，およびｎが１または２
の５〜６員環が好ましい。When R 1 and R 2 are adjacent to each other, R 1 and R 2 may be linked to form a ring represented by CH 2 m or —OCH 2 n O—, and such a ring is Includes a 5- to 7-membered ring formed with the carbon atoms of the benzene ring. Among these rings, m is a 5- or 6-membered ring having 3 or 4 and n is 1 or 2
Is preferably a 5- to 6-membered ring.
R3で示される低級アルキルとしては、前記R1およびR2
について記した炭素数が１〜６のものが好ましい。R3で
示されるアラルキルとしては、たとえばベンジル，フェ
ネチル等のフェニル−C1-4アルキルが好ましい。As the lower alkyl represented by R 3 , R 1 and R 2
Those having 1 to 6 carbon atoms described above are preferable. The aralkyl represented by R 3 is preferably, for example, phenyl-C 1-4 alkyl such as benzyl and phenethyl.
R4で示される置換されていてもよいアルキルにおける
アルキルとしては炭素数１〜10の直鎖状，分枝状，環状
いずれでもよく，その例としては、R1およびR2について
記したC1-6アルキルに加えて、たとえばヘプチル，オク
チル，ノニル，デシル，シクロプロピル，シクロブチ
ル，シクロペンチル，シクロヘキシル等が挙げられる。The alkyl in the optionally substituted alkyl represented by R 4 may be any of linear, branched and cyclic having 1 to 10 carbon atoms, and examples thereof include C 1 described for R 1 and R 2. In addition to -6 alkyl, for example, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned.
R4で示される置換されていてもよいアラルキルにおけ
るアラルキルとしては、R3で示されるアラルキルと同様
のものが挙げられる。The aralkyl in the optionally substituted aralkyl represented by R 4 includes the same aralkyl as the aralkyl represented by R 3 .
R4で示される置換されていてもよい芳香族基における
芳香族基としては、たとえばフェニル，ナフチル，アン
トリルおよびフェナントリル等のC6-14アリールが挙げ
られる。Examples of the aromatic group in the optionally substituted aromatic group represented by R 4 include C 6-14 aryl such as phenyl, naphthyl, anthryl and phenanthryl.
R4で示される置換されていてもよい複素環における複
素環としては、たとえば１個の硫黄原子，窒素原子また
は酸素原子を含む５〜７員複素環,2〜４個の窒素原子を
含む５〜６員複素環,1〜２個の窒素原子および１個の硫
黄原子または酸素原子を含む５〜６員複素環が挙げら
れ、これらの複素環は２個以下の窒素原子を含む６員
環，ベンゼン環または１個の硫黄原子を含む５員環と縮
合していてもよい。The heterocyclic ring in the optionally substituted heterocyclic ring represented by R 4 includes, for example, a 5- to 7-membered heterocyclic ring containing one sulfur atom, nitrogen atom or oxygen atom, and a 5- or 5-membered heterocyclic ring containing 2 to 4 nitrogen atoms. And 6-membered heterocycles containing 1 to 2 nitrogen atoms and 1 sulfur atom or 1 oxygen atom, and these heterocycles are 6-membered rings containing 2 or less nitrogen atoms. , A benzene ring or a 5-membered ring containing one sulfur atom.
上記の複素環の具体例としては、たとえば、２−ピリ
ジル,3−ピリジル,4−ピリジル，ピリミジル，ピラジニ
ル，ピリダジニル，ピラゾリル，イミダゾリル、チアゾ
リル，イソチアゾリル，オキサゾリル，イソキサゾリ
ル，ピリド［2,3−ｄ］ピリミジル，ベンゾピラニル,1,
8−ナフチリジル,1,5−ナフチリジル,1,6−ナフチリジ
ル,1,7−ナフチリジル,2,7−ナフチリジル,2,6−ナフチ
リジル，キノリル，チエノ［2,3−ｂ］ピリジル，テト
ラゾリル，チアジアゾリル，オキサジアゾリル，トリア
ジニル，トリアゾリル，チエニル，ピロリル，ピロリニ
ル，フリル，ピロリジニル，ベンゾチエニル，インドリ
ル，イミダゾリジニル，ピペリジル，ピペリジノ，ピペ
ラジニル，モルホリニル，モルホリノなどが挙げられ
る。Specific examples of the above heterocyclic ring include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido [2,3-d]. Pyrimidyl, benzopyranyl, 1,
8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl, thieno [2,3-b] pyridyl, tetrazolyl, thiadiazolyl, Examples include oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, morpholino, and the like.
R4で示される置換されていてもよいアルケニルにおけ
るアルケニルとしては炭素数２〜６のものが好ましく、
例としてはアリル（allyl），ビニル，クロチル,2−ペ
ンテン−１−イル,3−ペンテン−１−イル,2−ヘキセン
−１−イル,3−ヘキセン−１−イル,2−シクロヘキセニ
ル,2−シクロペンテニル,2−メチル−２−プロペン−１
−イル,3−メチル−２−ブテン−１−イル等が挙げられ
る。The alkenyl in the optionally substituted alkenyl represented by R 4 preferably has 2 to 6 carbon atoms,
Examples are allyl, vinyl, crotyl, 2-penten-1-yl, 3-penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-cyclohexenyl, 2 -Cyclopentenyl, 2-methyl-2-propene-1
-Yl, 3-methyl-2-buten-1-yl and the like.
上記R1またはR2で示される置換されていてもよいアル
キルにおける置換基としては、たとえばハロゲン（例、
フッ素，塩素，臭素，ヨウ素等），水酸基，炭素数１〜
６のアルコキシ（例、メトキシ，エトキシ，プロポキ
シ，イソプロポキシ，ブトキシ，ペンチルオキシ，ヘキ
シルオキシ等）などが挙げられ、置換基の数は１〜３個
が好ましい。Examples of the substituent in the optionally substituted alkyl represented by R 1 or R 2 include halogen (eg,
Fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, 1 to 1 carbon atoms
And 6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), and the number of substituents is preferably 1 to 3.
R1およびR2について置換された低級アルキルの具体例
としては、たとえばトリフルオロメチル，トリフルオロ
エチル，ジフルオロメチル，トリクロロメチル，ヒドロ
キシメチル,1−ヒドロキシエチル,2−ヒドロキシエチ
ル，メトキシメチル，エトキシメチル,1−メトキシエチ
ル,2−メトキシエチル,2−エトキシメチル,2,2−ジメト
キシエチル,2,2−ジエトキシエチルなどがあげられる。Specific examples of the lower alkyl substituted for R 1 and R 2 include, for example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxymethyl, ethoxymethyl , 1-methoxyethyl, 2-methoxyethyl, 2-ethoxymethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl and the like.
R4で示される置換されていてもよいアルキルにおける
置換基としては、たとえばハロゲン（例、フッ素，塩
素，臭素，ヨウ素等），水酸基，炭素数１〜６のアルコ
キシ，炭素数１〜６のアルキルまたは炭素数１〜10のア
シルで置換されていてもよいアミノ（例、ジメチルアミ
ノ，ジエチルアミノ，ジプロピルアミノ，アセチルアミ
ノ，プロピオニルアミノ，ベンゾイルアミノ等），炭素
数１〜６のアルキルで置換されていてもよいカルバモイ
ル（例、ジメチルカルバモイル，ジエチルカルバモイ
ル，ジプロピルカルバモイル等），炭素数１〜６のアル
コキシカルボニル（例、メトキシカルボニル，エトキシ
カルボニル，プロポキシカルボニル等），前記した複素
環などが挙げられる。R4について置換されたアルキルの
具体例としては、たとえばトリフルオロメチル，トリフ
ルオロエチル，ジフルオロメチル，トリクロロメチル,2
−ヒドロキシエチル,2−メトキシエチル,2−エトキシメ
チル,2,2−ジメトキシエチル,2,2−ジエトキシエチル,2
−ピリジルメチル,3−ピリジルメチル,4−ピリジルメチ
ル,2−（２−チエニル）エチル,3−（３−フリル）プロ
ピル,2−モルホリノエチル,3−ピロリルブチル,2−ピペ
リジノエチル,2−（N,N−ジメチルアミノ）エチル,2−
（Ｎ−メチル−Ｎ−エチルアミノ）エチル,2−（N,N−
ジイソプロピルアミノ）エチル,5−（N,N−ジメチルア
ミノ）ペンチル,N,N−ジエチルカルバモイルメチル,N,N
−ジメチルカルバモイルエチル,N,N−ジメチルカルバモ
イルペンチル，エトキシカルボニルメチル，イソプロポ
キシカルボニルエチル,tert−ブトキシカルボニルプロ
ピルなどが挙げられる。Examples of the substituent in the optionally substituted alkyl represented by R 4 include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms. Or an amino which may be substituted with an acyl having 1 to 10 carbons (eg, dimethylamino, diethylamino, dipropylamino, acetylamino, propionylamino, benzoylamino, etc.), or an alkyl substituted with 1 to 6 carbons. Carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, etc.), alkoxycarbonyl having 1 to 6 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), and the above-mentioned heterocycle. Specific examples of the alkyl substituted for R 4 include, for example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, 2
-Hydroxyethyl, 2-methoxyethyl, 2-ethoxymethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl, 2
-Pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-thienyl) ethyl, 3- (3-furyl) propyl, 2-morpholinoethyl, 3-pyrrolylbutyl, 2-piperidinoethyl, 2- (N, N-dimethylamino) ethyl, 2-
(N-methyl-N-ethylamino) ethyl, 2- (N, N-
Diisopropylamino) ethyl, 5- (N, N-dimethylamino) pentyl, N, N-diethylcarbamoylmethyl, N, N
-Dimethylcarbamoylethyl, N, N-dimethylcarbamoylpentyl, ethoxycarbonylmethyl, isopropoxycarbonylethyl, tert-butoxycarbonylpropyl and the like.
R4で示される置換されていてもよいアルキル、芳香族
基、複素環における置換基としては、たとえばハロゲン
（例、フッ素，塩素，臭素，ヨウ素等），炭素数１−６
のアルコキシ，炭素数１〜６のアルキル，ハロゲン化C
1-6アルキル（例、トリフルオロメチル，ジフルオロメ
チル,2,2,2−トリフルオロエチル,2,2,2−トリクロロエ
チル等），炭素数１−６のアルキルまたは炭素数１−10
のアシルで置換されていてもよいアミノ（例、メチルア
ミノ，ジメチルアミノ，ジエチルアミノ，ジブチルアミ
ノ，アセチルアミノ，プロピオニルアミノ，ベンゾイル
アミノ等），C1-6アルコキシで置換されていてもよいホ
スホリルまたはホスホリル−C1-6アルキル（例、ジエト
キシホスホリル，ジエトキシホスホリルメチル等），前
記したものと同様の芳香族基（ただしハロゲン置換され
ていてもよい。）などが挙げられる。Examples of the substituent in the optionally substituted alkyl, aromatic group, and heterocyclic ring represented by R 4 include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), C 1-6.
Alkoxy, alkyl having 1 to 6 carbon atoms, halogenated C
1-6 alkyl (eg, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc.), alkyl having 1 to 6 carbons or 1 to 10 carbons
Amino optionally substituted with acyl (eg, methylamino, dimethylamino, diethylamino, dibutylamino, acetylamino, propionylamino, benzoylamino), phosphoryl or phosphoryl optionally substituted with C 1-6 alkoxy —C 1-6 alkyl (eg, diethoxyphosphoryl, diethoxyphosphorylmethyl, etc.), and the same aromatic groups as described above (but may be halogen-substituted).
R4について、置換されたアラルキルの具体例として
は、たとえば４−クロロベンジル,3−（２−フルオロフ
ェニル）プロピル,3−メトキシベンジル,3,4−ジメトキ
シフェネチル,4−エチルベンジル,3,4−ジメチルフェネ
チル,3−トリフルオロメチルベンジル,4−（３−トリフ
ルオロフェニル）ブチル,4−アセチルアミノベンジル,2
−プロピオニルアミノフェネチル等が挙げられる。Specific examples of the substituted aralkyl for R 4 include, for example, 4-chlorobenzyl, 3- (2-fluorophenyl) propyl, 3-methoxybenzyl, 3,4-dimethoxyphenethyl, 4-ethylbenzyl, 3,4 -Dimethylphenethyl, 3-trifluoromethylbenzyl, 4- (3-trifluorophenyl) butyl, 4-acetylaminobenzyl, 2
-Propionylaminophenethyl and the like.
R4について、置換された芳香族基の具体例としては、
たとえば４−クロロフェニル,2,4−ジフルオロフェニ
ル,6−メトキシ−２−ナフチル,3,4−ジエトキシフェニ
ル,3,4−ジメチルフェニル,3−トリフルオロフェニル,4
−シクロヘキシルフェニル,4−アセチルアミノフェニ
ル,2−ベンゾイルアミノフェニル,4−ジエトキシホスホ
リルフェニル,4−ジエトキシホスホリルメチルフェニル
等があげられる。For R 4, specific examples of the substituted aromatic group,
For example, 4-chlorophenyl, 2,4-difluorophenyl, 6-methoxy-2-naphthyl, 3,4-diethoxyphenyl, 3,4-dimethylphenyl, 3-trifluorophenyl, 4
-Cyclohexylphenyl, 4-acetylaminophenyl, 2-benzoylaminophenyl, 4-diethoxyphosphorylphenyl, 4-diethoxyphosphorylmethylphenyl and the like.
R4について、置換された複素環の具体例としては、た
とえば５−クロロ−２−ピリジル,3−メトキシ−２−ピ
リジル,5−メチル−２−ベンゾチアゾリル,5−メチル−
４−フェニル−２−チアゾリル,3−フェニル−５−イソ
オキサゾリル,4−（４−クロロフェニル）−５−メチル
−２−オキサゾリル,4−ブチル−１−ピペラジニル,3−
フェニル−1,2,4−チアジアゾール−５−イル,5−メチ
ル−1,3,4−チアジアゾール−２−イル,5−アセチルア
ミノ−２−ピリミジル,3−メチル−２−チエニル,4,5−
ジメチル−２−フラニル,4−メチル−２−モルホリニル
等が挙げられる。Specific examples of the substituted heterocycle for R 4 include, for example, 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, 5-methyl-2-benzothiazolyl, 5-methyl-
4-phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl, 4- (4-chlorophenyl) -5-methyl-2-oxazolyl, 4-butyl-1-piperazinyl, 3-
Phenyl-1,2,4-thiadiazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl, 4,5 −
Dimethyl-2-furanyl, 4-methyl-2-morpholinyl and the like.
R4で示される置換されていてもよいアルケニルにおけ
る置換基としては、R4で示される置換されていてもよい
アルキルにおける置換基と同じものが挙げられる。Examples of the substituent in the alkenyl which may be substituted represented by R 4, the same as those of a substituent in the alkyl group which may be substituted represented by R 4.
R4について、置換されたアルケニルの具体例としては2,
2−ジフルオロビニル,4−エトキシクロチル,1−シクロ
ヘキセニルメチル,3−シクロヘキシル−２−ブテン−１
−イル,4−（２−ピリジル）−２−ブテン−１−イル,4
−（N,N−ジエチルアミノ）クロチル,3−（５−メチル
−２−フェニル−４−オキサゾリル）−２−プロペン−
１−イル,4−（N,N−ジメチルカルバモイル）クロチル
等が挙げられる。For R 4, 2 Specific examples of the substituted alkenyl,
2-difluorovinyl, 4-ethoxycyclotyl, 1-cyclohexenylmethyl, 3-cyclohexyl-2-butene-1
-Yl, 4- (2-pyridyl) -2-buten-1-yl, 4
-(N, N-diethylamino) crotyl, 3- (5-methyl-2-phenyl-4-oxazolyl) -2-propene-
1-yl, 4- (N, N-dimethylcarbamoyl) crotyl and the like.
上記化合物（Ｉ）のうちR4がメチル，エチルまたはベ
ンジルである時，R1，R2およびR3のうち少なくとも１つ
は置換されている化合物は新規化合物である。When R 4 is methyl, ethyl or benzyl in the compound (I), a compound in which at least one of R 1 , R 2 and R 3 is substituted is a novel compound.
上記化合物（Ｉ）はたとえば次の様にして製造でき
る。すなわち Ａ法 一般式 ［式中、R1，R2，R3およびR4は前記と同意義を有する］
で表わされる化合物を適当な溶媒中、あるいは溶媒なし
で加熱することにより得ることができる。かかる溶媒と
しては、たとえばメタノール，エタノール，プロパノー
ル,2−プロパノール，ブタノール,2−メトキシエタノー
ルなどのアルコール類，ジオキサン，テトラヒドロフラ
ン，ジメトキシエタンなどのエーテル類，ベンゼン，ト
ルエン，キシレンなどの芳香族炭化水素類，酢酸エチ
ル，アセトニトリル，ピリジン,N,N−ジメチルホルムア
ミド，ジメチルスルホキシド，クロロホルム，ジクロル
メタン,1,2−ジクロルエタン,1,1,2,2−テトラクロルエ
タンあるいはこれらの混合溶媒などがあげられる。本反
応においては適宜の塩素、たとえば炭酸カリウム，トリ
エチルアミン,N−メチルモルホリン,N,N−ジメチルアミ
ノピリジン,N,N−ジメチルアニリン，ピリジンなどの存
在下に行うこともできる。塩素の使用量は化合物（II）
１モルに対し0.1〜10モル程度が好ましい。反応温度は
いずれの場合も約10℃〜約200℃、好ましくは約20℃〜
約150℃であり、反応時間は、通常約0.5〜100時間、好
ましくは約２〜20時間である。The above compound (I) can be produced, for example, as follows. That is, method A general formula [Wherein R 1 , R 2 , R 3 and R 4 have the same meaning as described above]
Can be obtained by heating the compound represented by the formula (1) in a suitable solvent or without a solvent. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, and 2-methoxyethanol; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane or a mixed solvent thereof. This reaction can also be carried out in the presence of appropriate chlorine, for example, potassium carbonate, triethylamine, N-methylmorpholine, N, N-dimethylaminopyridine, N, N-dimethylaniline, pyridine and the like. The amount of chlorine used is compound (II)
It is preferably about 0.1 to 10 mol per 1 mol. The reaction temperature is in each case about 10 ° C to about 200 ° C, preferably about 20 ° C to
The reaction time is usually about 0.5 to 100 hours, preferably about 2 to 20 hours.
Ｂ法 本法ではＡ法において、化合物（II）のうちR4が水素
である化合物（II−１）を用いて得られた化合物
（Ｉ′） ［式中、R1，R2およびR3は前記と同意義を有する］と式 R4′−Ｘ （III） ［式中、R4′はそれぞれ置換されていてもよいアルキ
ル、アラルキルまたはアルケニルを示し、Ｘは脱離基を
示す］で表わされる化合物（III）とを反応させること
により得ることができる。R4′で示される置換されてい
てもよいアルキル、アラルキルおよびアルケニルは前記
R4で示されるそれらと同様のものがあげられる。またＸ
で示される脱離基としては、たとえばハロゲン，好まし
くは塩素，臭素またはヨウ素やエステル化することによ
り活性化されたヒドロキシル基，たとえば有機スルホン
酸の残基であるアリールスルホニルオキシ基（例、ｐ−
トルエンスルホニルオキシ基，ベンゼンスルホニルオキ
シ基），炭素数１−４のアルキルスルホニルオキシ基
（例、メタンスルホニルオキシ基）や、有機リン酸の残
基であるジフェニルフォスフォリルオキシ基，ジベンジ
ルフォスフォリルオキシ基，炭素数１−４のジアルキル
フォスフォリルオキシ基（例、ジメチルフォスフォリル
オキシ基）などが挙げられる。本反応は有機溶媒中、塩
基の存在下に反応させることにより行なわれる。溶媒と
しては用いる塩基の種類によっても異なるが、たとえば
メタノール，エタノールなどのアルコール類，テトラヒ
ドロフラン，ジオキサン，ジメトキシエタン，ジエチル
エーテルなどのエーテル類,N,N−ジメチルホルムアミ
ド，ジメチルスルホキシドなどが適宜用いることができ
る。塩基としてはたとえば炭酸カリウム，炭酸ナトリウ
ム，炭酸水素ナトリウム，ナトリウムメトキシド，ナト
リウムエトキシド，カリウムｔ−ブトキシド，水素化ナ
トリウム，水素化カリウム，ナトリウムアミドなどが用
いられる。本反応ではまず化合物（Ｉ′）と塩基とを溶
媒中で反応させてアニオンを形成させ、ついで化合物
（III）を反応させるのが好ましい。反応温度は通常約1
0℃〜約100℃、好ましくは約０℃〜約40℃、反応時間は
通常約0.5〜10時間、好ましくは約１〜５時間である。Method B In this method, compound (I ′) obtained by using compound (II-1) of compound (II) wherein R 4 is hydrogen in method A [Wherein R 1 , R 2 and R 3 have the same meaning as described above] and R 4 ′ -X (III) wherein R 4 ′ is an optionally substituted alkyl, aralkyl or alkenyl And X represents a leaving group], and the compound (III) represented by the following formula: The optionally substituted alkyl, aralkyl and alkenyl represented by R 4 ′ are as defined above.
The same as those shown by R 4 can be mentioned. Also X
The leaving group represented by is, for example, halogen, preferably chlorine, bromine or iodine, or a hydroxyl group activated by esterification, for example, an arylsulfonyloxy group which is a residue of an organic sulfonic acid (eg, p-
A toluenesulfonyloxy group, a benzenesulfonyloxy group), an alkylsulfonyloxy group having 1 to 4 carbon atoms (eg, a methanesulfonyloxy group), a diphenylphosphoryloxy group, a dibenzylphosphoryl group which is a residue of an organic phosphoric acid. And a dialkylphosphoryloxy group having 1 to 4 carbon atoms (eg, dimethylphosphoryloxy group). This reaction is carried out in an organic solvent in the presence of a base. Although the solvent varies depending on the type of base used, for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethyl ether, N, N-dimethylformamide, dimethylsulfoxide, and the like are appropriately used. it can. As the base, for example, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, potassium hydride, sodium amide and the like are used. In this reaction, it is preferable to first react the compound (I ') with a base in a solvent to form an anion, and then to react the compound (III). The reaction temperature is usually about 1
0 ° C to about 100 ° C, preferably about 0 ° C to about 40 ° C, and the reaction time is usually about 0.5 to 10 hours, preferably about 1 to 5 hours.
Ｃ法 本法ではＡ法において、化合物（II）のうちR3が水素
である化合物（II−２）を用いてあるいはＢ法におい
て、化合物（Ｉ′）のうちR3が水素である化合物（Ｉ′
−１）を用いて得られた下式化合物（Ｉ″） ［式中、R1，R2およびR4は前記と同意義を有する］で表
わされる化合物と 式 R3′−Ｘ（IV） ［式中、R3′は低級アルキルまたはアラルキルを示し、
Ｘは前記と同意義を有する。］で表わされる化合物（I
V）とを反応させることにより得ることができる。R3′
で示される低級アルキルおよびアラルキルは前記R3で示
されるそれらと同様のものが挙げられる。本反応はＢ法
における化合物（Ｉ′）と化合物（III）との反応とま
ったく同様の条件下で行うことができる。Method C In this method, in method A, compound (II-2) in which R 3 is hydrogen in compound (II) is used, or in method B, compound (I ′) in which R 3 is hydrogen ( I '
The following compound (I ″) obtained using -1) Wherein R 1 , R 2 and R 4 are as defined above, and a compound represented by the formula R 3 ′ -X (IV) wherein R 3 ′ represents lower alkyl or aralkyl;
X has the same meaning as described above. (I)
V). R 3 ′
The lower alkyl and aralkyl represented by the same as those represented by the above R 3 can be mentioned. This reaction can be carried out under exactly the same conditions as in the reaction of compound (I ') with compound (III) in Method B.
このようにして得られる1,2,4−ベンゾチアジアジン
誘導体（Ｉ）は公知の分離精製手段たとえば濃縮、減圧
濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフ
ィーなどにより単離精製することができる。The 1,2,4-benzothiadiazine derivative (I) thus obtained is isolated by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. It can be purified.
本発明の原料化合物（II）はたとえばつぎのＤ法に示
すような方法で製造することができる。The starting compound (II) of the present invention can be produced, for example, by the method shown in the following Method D.
［式中、R1〜R4およびＸは前記と同意義を有する］ 本法ではまず（Ｖ）をアリル（allyl）化して（VII）
とし、ついでイソシアナート類（VIII）と反応させてウ
レイド誘導体（IX）とし、（Ｘ）と反応させた後、酸化
して（II）を製造する。（Ｖ）と（VI）の反応は適宜の
溶媒中で行なわれる。該溶媒としては例えばベンゼン、
トルエン、キシレンなどの芳香族炭化水素、ジオキサ
ン、テトラヒドロフラン、ジメトキシエタンなどのエー
テル類、メタノール、エタノール、プロパノールなどの
アルコール類、酢酸エチル、アセトニトリル、ピリジ
ン、N,N−ジメチルホルムアミド、ジメチルスルフォキ
シド、クロロホルム、ジクロロメタン、1,2−ジクロロ
メタン、1,1,2,2−テトラクロロエタンあるいは水、及
びこれらの混合溶媒があげられる。塩基としては水酸化
ナトリウム、水酸化カリウム、炭酸カリウム、炭酸ナト
リウムなどのアルカリ金属塩、ピリジン、トリエチルア
ミン、N,N−ジメチルアニリンなどのアミン類などがあ
げられる。本反応は通常約−10〜150℃、好ましくは約
０〜50℃で行われる。 [In the formula, R 1 to R 4 and X have the same meanings as described above.] In the present method, first, (V) is allylated to form (VII)
Then, it is reacted with isocyanates (VIII) to give ureide derivatives (IX), reacted with (X), and then oxidized to produce (II). The reaction between (V) and (VI) is performed in an appropriate solvent. As the solvent, for example, benzene,
Toluene, aromatic hydrocarbons such as xylene, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, alcohols such as methanol, ethanol, propanol, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, Examples include chloroform, dichloromethane, 1,2-dichloromethane, 1,1,2,2-tetrachloroethane or water, and a mixed solvent thereof. Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, and amines such as pyridine, triethylamine, and N, N-dimethylaniline. This reaction is generally carried out at about -10 to 150C, preferably at about 0 to 50C.
（VII）とイソシアナート類（VIII）との反応は適宜
の溶媒中で行なわれる。The reaction of (VII) with isocyanates (VIII) is carried out in a suitable solvent.
該溶媒としてはたとえばベンゼン、トルエン、キシレ
ンなどの芳香族炭化水素、ジオキサン、テトラヒドロフ
ラン、ジメトキシエタンなどのエーテル類、メタノー
ル、エタノール、プロパノールなどのアルコール類、酢
酸エチル、アセトニトリル、ピリジン、N,N−ジメチル
ホルムアミド、ジメチルスルホキシド、クロロホルム、
ジクロルメタン、1,2−ジクロルメタン、1,1,2,2−テト
ラクロルエタン；酢酸，水あるいはこれらの混合溶媒が
あげられる。本反応は通常約−10℃〜150℃、好ましく
は約20℃〜100℃で約0.5〜20時間反応させて行なわれ
る。Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine and N, N-dimethyl. Formamide, dimethyl sulfoxide, chloroform,
Dichloromethane, 1,2-dichloromethane, 1,1,2,2-tetrachloroethane; acetic acid, water or a mixed solvent thereof. This reaction is carried out usually at about -10 ° C to 150 ° C, preferably at about 20 ° C to 100 ° C for about 0.5 to 20 hours.
ついで得られた（IX）と化合物（Ｘ）とを反応させて
（XI）を製造する。本反応工程はＢ法における化合物
（Ｉ′）と化合物（III）との反応とまったく同様にし
て行うことができる。Then, the obtained (IX) is reacted with the compound (X) to produce (XI). This reaction step can be carried out in exactly the same manner as in the reaction of compound (I ') with compound (III) in Method B.
さらに（XI）を酸化して化合物（II）を製造する。水
酸化反応は常法に従い、酸化剤、例えばｍ−クロロ過安
息香酸、過酸化水素、過エステル（peresters）、メタ
過ヨウ素酸ナトリウム等を用いて行なわれる。この酸化
は反応条件下で不活性である有機溶媒、例えばハロゲン
化された炭化水素（例、塩化メチレン、クロロホルム，
ジクロロエタン等）、または炭化水素（例、ベンゼン，
トルエン等），アルコール類（メタノール，エタノー
ル，プロパノール等）中にて有利に行なわれる。酸化剤
として過酸化水素を用いる場合、また酸化を酢酸、水性
酢酸中にて行なうことができる。酸化剤はやや過剰に用
いることが好ましい。本反応は室温またはこれ以下、好
ましくは約−50℃〜10℃の温度で通常約0.5〜10時間か
けて行なわれる。Further, (XI) is oxidized to produce compound (II). The hydroxylation reaction is carried out according to a conventional method using an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, peresters, sodium metaperiodate and the like. This oxidation is carried out in an organic solvent which is inert under the reaction conditions, such as halogenated hydrocarbons (eg, methylene chloride, chloroform,
Dichloroethane, etc.) or hydrocarbons (eg, benzene,
It is advantageously carried out in an alcohol (methanol, ethanol, propanol, etc.). When using hydrogen peroxide as the oxidizing agent, the oxidation can be carried out in acetic acid or aqueous acetic acid. The oxidizing agent is preferably used in a slightly excessive amount. This reaction is carried out at room temperature or below, preferably at a temperature of about -50 ° C to 10 ° C, usually for about 0.5 to 10 hours.
ウレイド誘導体（IX）は、また次の方法で得ることも
できる。The ureide derivative (IX) can also be obtained by the following method.
本法では、まず安息香酸誘導体（XII）を通常のクル
チウム転位反応によりイソシアナート類（XIII）とす
る。本反応は、任意の公知の方法に従えばよく、例えば
新実験化学講座，第14巻，「有機化合物の合成と反応
［III］」（1978年）等に記載の方法あるいはそれに準
じた方法により行なわれる。例えば塩化オキサリルまた
は塩化チオニル等により（XII）を酸塩化物とし、つい
でナトリウムアジドとの反応で酸アジドとする。酸アジ
ドをベンゼン，トルエンまたはジフェニルエーテル等の
溶媒中で加熱することによりイソシアナート類（XIII）
が得られる。ついで（XIII）をアミン類（XIV）と反応
させウレイド誘導体（IX）を製造する。本反応工程はＤ
法における化合物（VII）と化合物（VIII）とを反応さ
せる場合の反応条件とまったく同様にして行うことがで
きる。 In the present method, first, the benzoic acid derivative (XII) is converted to an isocyanate (XIII) by a usual curtium rearrangement reaction. This reaction may be performed according to any known method, for example, by the method described in New Experimental Chemistry, Vol. 14, “Synthesis and Reaction of Organic Compounds [III]” (1978) or a method analogous thereto. Done. For example, (XII) is converted to an acid chloride with oxalyl chloride or thionyl chloride or the like, and then converted to an acid azide by reaction with sodium azide. Isocyanates (XIII) by heating acid azide in a solvent such as benzene, toluene or diphenyl ether
Is obtained. Then, (XIII) is reacted with an amine (XIV) to produce a ureide derivative (IX). This reaction step is D
The reaction can be carried out exactly in the same manner as in the reaction of compound (VII) with compound (VIII) in the method.
以下に化合物（Ｉ）の薬理効果を示す試験結果を示
す。The test results showing the pharmacological effects of compound (I) are shown below.
［骨吸収抑制作用］ 骨吸収作用の測定はロイスの方法［ジャーナル・オブ
・クリニカル・インベスティゲーション（J.Clin.Inves
t.）44,103-116（1965）］によった。すなわち、妊娠19
日目のSprague-Dawle系ラット１匹に45Ca（カルシウム
の同位元素，CaCl2溶液）を50μ Ci皮下注射し、翌日開
腹し、無菌的に胎児ラットを取り出し、解剖顕微鏡下で
胎児ラットの左右の前腕骨（橈骨，尺骨）を躯幹より切
り離しさらに可能な限り結合織，軟骨を除いて骨培養サ
ンプルとした。骨を一片ずつ0.6mlのBGJbメディウム（F
itton-Jackson modification,［GIBCO Laboratories
（米国）］に牛血清アルブミン,2mg/mlを含む）中で37
℃で24時間前培養した後、後述する実施例で得られた化
合物を10μ/gmlとなるように加えた上記メディウムでさ
らに２日間培養をつづけた後、メディウム中の45Caの放
射活性と骨中の45Caの放射活性を測定し、次式に従っ
て、骨からメディウム中へ放出した45Caの比率（％）を
求めた。[Bone resorption inhibitory action] The bone resorption action was measured by the method of Royce [Journal of Clinical Investigation (J. Clin. Inves).
t.) 44 , 103-116 (1965)]. That is, pregnant 19
One Sprague-Dawle rat on the day was subcutaneously injected with 45 Ca (calcium isotope, CaCl 2 solution) at 50 μCi, the laparotomy was performed on the next day, and the fetal rat was aseptically removed. The forearm bones (radius, ulna) were cut off from the trunk, and the connective tissue and cartilage were removed as much as possible to obtain bone culture samples. 0.6 ml of BGJ b medium (F
itton-Jackson modification, [GIBCO Laboratories
(USA)] containing bovine serum albumin, 2 mg / ml)
After culturing at 24 ° C. for 24 hours, culturing was continued for another 2 days with the above-mentioned medium to which the compound obtained in the following example was added to 10 μ / g ml, and then radioactivity of 45 Ca in the medium and bone The radioactivity of 45 Ca in the medium was measured, and the ratio (%) of 45 Ca released from the bone into the medium was determined according to the following equation.
同腹の胎児から得た骨を化合物を加えないで同様に２
日間培養したものを対照群とした。各群５個の骨から得
られた値の平均値±標準偏差を求め、この値の対照群の
値に対する比率（％）を求めその結果を第１表に示し
た。 Bone obtained from a litter of the same litter
Those cultured for days were used as a control group. The average value ± standard deviation of the values obtained from 5 bones in each group was determined, and the ratio (%) of this value to the value of the control group was determined. The results are shown in Table 1.
また、化合物（Ｉ）の毒性については、たとえば実施
例No.3,No.4,No.11またはNo.12で合成した化合物を300m
g/kg・体重の割合でマウスに経口投与しても、死亡例は
認められなかった。 Regarding the toxicity of the compound (I), for example, the compound synthesized in Example No. 3, No. 4, No. 11 or No.
No oral death was observed in mice administered orally at a ratio of g / kg · body weight.
上記した様に、本発明における化合物（Ｉ）はすぐれ
た骨吸収抑制作用を有し、かつ毒性が低い。As described above, the compound (I) of the present invention has an excellent inhibitory action on bone resorption and has low toxicity.
したがって、本発明の化合物（Ｉ）は、哺乳動物
（例、マウス，ラット，ウサギ，犬，ネコ，牛，豚、ヒ
ト等）の骨粗鬆症の予防および治療に用いることができ
る。Therefore, the compound (I) of the present invention can be used for prevention and treatment of osteoporosis in mammals (eg, mice, rats, rabbits, dogs, cats, cows, pigs, humans, etc.).
本発明の化合物（Ｉ）を、哺乳動物の骨粗鬆症の予防
または治療剤として用いるには、たとえば化合物（Ｉ）
を薬理学的に許容され得る担体、たとえば賦形剤（例、
乳糖，澱粉，ショ糖等），崩壊剤（例、澱粉，カルボキ
シメチルセルロースカルシウム等），滑沢剤（例、ステ
アリン酸マグネシウム，タルク等）結合剤（例、ヒドロ
キシプロピルセルロース，ヒドロキシプロピルメチルセ
ルロース，マクロゴール等）等と適宜混合し、カプセル
剤，錠剤，顆粒剤，散剤などの剤型にして経口的に投与
することができる。In order to use the compound (I) of the present invention as an agent for preventing or treating osteoporosis in mammals, for example, the compound (I)
A pharmacologically acceptable carrier such as an excipient (eg,
Lactose, starch, sucrose, etc.), disintegrant (eg, starch, carboxymethylcellulose calcium, etc.), lubricant (eg, magnesium stearate, talc, etc.) binder (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol) And the like, and orally administered in the form of capsules, tablets, granules, powders and the like.
また非経口的に投与する場合には、化合物（Ｉ）を通
常液剤に用いられる添加剤、例えばpH調整用の緩衝剤
（リン酸緩衝剤、ホウ酸緩衝剤、クエン酸緩衝剤、酒石
酸緩衝剤、酢酸緩衝剤等）、等張化剤（ソルビトール、
グリセリン、ポリエチレングリコール、プロピレングリ
コール、グルコース、塩化ナトリウム等）、防腐殺菌剤
（パラオキシ安息香酸エステル類、ベンジルアルコー
ル、パラクロルメタキシノール、クロルクレゾール、フ
ェネチルアルコール、ソルビン酸またはその塩、チメロ
サール、クロロブタノール、パラベン類等）、キレート
剤（エデト酸ナトリウム、クエン酸ナトリウム、縮合リ
ン酸ナトリウム等）、粘稠剤（カルボキシメチルセルロ
ース、ナトリウム、ヒドロキシエチルセルロース、ヒド
ロキシプロピルセルロース、メチルセルロース、ポリビ
ニルアルコール、ポリアクリル酸ナトリウム）などを、
通常使用される添加量で配合し、注射剤として、または
化合物（Ｉ）をたとえば中鎖もしくは高級脂肪酸のトリ
グリセライド，ポリエチレングリコールなどを、通常使
用される添加量で配合し、成型することにより坐剤とし
てもよい。In the case of parenteral administration, compound (I) may be added to an additive usually used in a liquid preparation, for example, a buffer for adjusting pH (phosphate buffer, borate buffer, citrate buffer, tartrate buffer, etc.). , Acetate buffer, etc.), tonicity agent (sorbitol,
Glycerin, polyethylene glycol, propylene glycol, glucose, sodium chloride, etc., preservatives and disinfectants (paraoxybenzoic acid esters, benzyl alcohol, parachloromethxinol, chlorcresol, phenethyl alcohol, sorbic acid or its salts, thimerosal, chlorobutanol) , Parabens), chelating agents (sodium edetate, sodium citrate, condensed sodium phosphate, etc.), thickeners (carboxymethylcellulose, sodium, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, sodium polyacrylate) Etc.
Suppositories may be prepared by mixing the compound (I) with a commonly used amount, for example, triglyceride of medium-chain or higher fatty acid, polyethylene glycol or the like, and molding the compound (I) as an injection. It may be.
投与量は、経口的に投与する場合は、成人１人につき
通常１日あたり約10mg〜1g、好ましくは約10mg〜100mg
であり、非経口的に投与する場合は成人１人につき通常
１日あたり約0.1mg〜100mg、好ましくは約0.1mg〜10mg
である。The dose is, when administered orally, usually about 10 mg to 1 g per day, preferably about 10 mg to 100 mg per adult person.
When administered parenterally, usually about 0.1 mg to 100 mg per day per adult, preferably about 0.1 mg to 10 mg per adult
It is.
実施例 つぎに参考例および実施例をあげて本発明をさらに具
体的に説明する。なお、融点はすべて熱板法で測定し未
補正である。EXAMPLES Next, the present invention will be described more specifically with reference to Reference Examples and Examples. All melting points were measured by the hot plate method and are uncorrected.
参考例１ ２−アミノチオフェノール（200g）,6N NaOH（267m
l）及びMeOH（200ml）の混合物に氷冷下アリルブロミド
（194g）を１時間かけて滴下した。さらに1.5時間撹拌
後、水を加えてエーテルで抽出した。エーテル層を水
洗、乾燥（MgSO4）後、溶媒を留去、残留物を減圧蒸留
に付し２−アリルチオアニリン（256.8g,97.1％）を得
た。bp 108-114℃/4mm Hg.NMR（δ ppm in CDCl3）:3.3
4（2H,d,J＝７）,4.33（2H,br s）,4.8-5.1（2H,m）,5.
6-6.1（1H,m）,6.5-6.8（2H,m）,7.09（1H,double t,J
＝7.5and2）,7.33（1H,double d,J＝7.5 and 2） 参考例２〜９ 同様にして第２表の化合物を得た。Reference Example 1 2-aminothiophenol (200 g), 6N NaOH (267 m
Allyl bromide (194 g) was added dropwise to a mixture of l) and MeOH (200 ml) under ice cooling over 1 hour. After stirring for an additional 1.5 hours, water was added and extracted with ether. After the ether layer was washed with water and dried (MgSO 4 ), the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 2-allylthioaniline (256.8 g, 97.1%). bp 108-114 ° C / 4mm Hg. NMR (δ ppm in CDCl 3 ): 3.3
4 (2H, d, J = 7), 4.33 (2H, brs), 4.8-5.1 (2H, m), 5.
6-6.1 (1H, m), 6.5-6.8 (2H, m), 7.09 (1H, double t, J
= 7.5 and 2), 7.33 (1H, double d, J = 7.5 and 2) Reference Examples 2 to 9 The compounds in Table 2 were obtained in the same manner.
参考例10 ２−アリルチオ−５−トリフルオロメチルアニリン
（1.7g），フェニルイソシアナート（1.1g），トルエン
（7ml）の混合物を２時間かきまぜた。減圧下に溶媒を
留去し、残留する結晶をろ取した。イソプロピルエーテ
ルから再結晶し、Ｎ−（２−アリルチオ−５−トリフル
オロメチルフェニル）−Ｎ′−フェニルウレアを無色結
晶として得た。 Reference Example 10 A mixture of 2-allylthio-5-trifluoromethylaniline (1.7 g), phenyl isocyanate (1.1 g), and toluene (7 ml) was stirred for 2 hours. The solvent was distilled off under reduced pressure, and the remaining crystals were collected by filtration. Recrystallization from isopropyl ether gave N- (2-allylthio-5-trifluoromethylphenyl) -N'-phenylurea as colorless crystals.
収量2.1g（81.0％）。mp135-136℃。Yield 2.1 g (81.0%). mp 135-136 ° C.
元素分析値C17H15F3N2OSとして 計算値:C,57.95;H,4.29;N,7.95 実測値:C,58.07;H,4.39;N,7.88 参考例11-29 参考例10と同様にして第３表の化合物を得た。Elemental analysis C 17 H 15 F 3 N 2 OS Calculated: C, 57.95; H, 4.29 ; N, 7.95 Found: C, 58.07; H, 4.39 ; N, and 7.88 Reference Example 11-29 Reference Example 10 Similarly, the compounds shown in Table 3 were obtained.
参考例30 ２−アリルチオ−６−エチルアニリン（6.0g）の酢酸
（20ml）溶液にシアン酸カリウム（3.0g）の水（10ml）
溶液を60℃で滴下した。同温度で30分かきまぜた後、水
を加え折出した結晶をろ取した。酢酸エチル−ヘキサン
から再結晶しＮ−（２−アリルチオ−６−エチルフェニ
ル）ウレアを無色結晶として得た。収量5.8g（79.0
％）．融点163-164℃。 Reference Example 30 To a solution of 2-allylthio-6-ethylaniline (6.0 g) in acetic acid (20 ml) was added potassium cyanate (3.0 g) in water (10 ml).
The solution was added dropwise at 60 ° C. After stirring at the same temperature for 30 minutes, water was added and the precipitated crystals were collected by filtration. Recrystallization from ethyl acetate-hexane gave N- (2-allylthio-6-ethylphenyl) urea as colorless crystals. Yield 5.8g (79.0
%). 163-164 ° C.
元素分析値C12H16N2OSとして 計算値:C,60.99;H,6.82;N,11.85 実測値:C,61.07;H,6.83;N,11.91 参考例31-37 参考例30と同様にして第４表の化合物を得た。Elemental analysis value as C 12 H 16 N 2 OS Calculated value: C, 60.99; H, 6.82; N, 11.85 Actual value: C, 61.07; H, 6.83; N, 11.91 Reference Examples 31-37 Same as Reference Example 30 Thus, the compounds shown in Table 4 were obtained.
参考例38 Ｎ−（２−アリルチオフェニル）ウレア（3.12g）のD
MF（15ml）溶液に油性水素化ナトリウム（0.6g）を加
え、水冷下15分間、ついで室温で15分間かきまぜた。再
び氷冷し、ヨウ化メチル（0.93ml）を加え1.5時間かき
まぜた。反応混合物を水に注ぎ酢酸エチルで抽出した。
酢酸エチル層は水洗、乾燥（MgSO4）後、溶媒を留去、
残留物をカラムクロマトグラフィー［シリカゲル（100
g），酢酸エチルで溶出］で精製した。Ｎ−（２−アリ
ルチオフェニル）−Ｎ−メチルウレアを油状物として得
た。収量2.84g（85.3％）。NMR（δ ppm in CDCl3）:3.
17（3H,s）,3.56（2H,d,J＝6.5Hz）,4.38（2H,br s）,
5.03-5.40（m,2H）,5.66-6.20（m,1H）,7.17-7.47（m,4
H） IR（neat）:3476,3320,3200,1660cm1 元素分析値C11H14N2OSとして 計算値:C,59.43;H,6.35;N,12.60 実測値:C,59.22;H,6.42;N,12.45 参考例39 参考例38と同様にしてＮ−（２−アリルチオフェニ
ル）−Ｎ−ベンジルウレアを得た。収率69.4％。酢酸エ
チル−ヘキサンから再結晶。無色板状晶。mp.112-112
℃。 Reference Example 38 D of N- (2-allylthiophenyl) urea (3.12 g)
Oily sodium hydride (0.6 g) was added to the MF (15 ml) solution, and the mixture was stirred under water cooling for 15 minutes and then at room temperature for 15 minutes. The mixture was ice-cooled again, methyl iodide (0.93 ml) was added, and the mixture was stirred for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried (MgSO 4 ), and the solvent was distilled off.
The residue was subjected to column chromatography [silica gel (100
g), eluted with ethyl acetate]. N- (2-allylthiophenyl) -N-methylurea was obtained as an oil. Yield 2.84 g (85.3%). NMR (δ ppm in CDCl 3 ): 3.
17 (3H, s), 3.56 (2H, d, J = 6.5Hz), 4.38 (2H, brs),
5.03-5.40 (m, 2H), 5.66-6.20 (m, 1H), 7.17-7.47 (m, 4
H) IR (neat): 3476, 3320, 3200, 1660 cm 1 Elemental analysis value calculated as C 11 H 14 N 2 OS Calculated value: C, 59.43; H, 6.35; N, 12.60 Actual value: C, 59.22; H, 6.42 N, 12.45 Reference Example 39 N- (2-allylthiophenyl) -N-benzylurea was obtained in the same manner as in Reference Example 38. Yield 69.4%. Recrystallized from ethyl acetate-hexane. Colorless platelets. mp.112-112
° C.
元素分析値C17H18N2OSとして 計算値:C,68.43;H,6.08;N,9.39 実測値:C,68.73;H,6.13;N,9.45 参考例40 Ｎ−（２−アリルチオ−５−トリフルオロメチルフェ
ニル）−Ｎ′−tert−ブチルウレア（0.6g）のクロロホ
ルム（15ml）溶液に氷冷下ｍ−クロロ過安息香酸（含量
80％,0.39g）のクロロホルム（6ml）溶液を滴下した。
反応液を飽和炭酸水素ナトリウム水溶液、水の順に洗浄
後乾燥した。溶媒を留去し残留物はカラムクロマトグラ
フィー［シリカゲル（30g），酢酸エチル−ヘキサン
（1:2）溶出］で精製し、イソプロピルエーテル−ヘキ
サンから再結晶して20（アリルスルフィニル−５−トリ
フルオロメチルフェニル）−Ｎ′−tert−ブチルウレア
の無色針状晶を得た。収量0.59g（94.0％）。mp.113-11
4℃。Elemental analysis: as C 17 H 18 N 2 OS Calculated: C, 68.43; H, 6.08; N, 9.39 Found: C, 68.73; H, 6.13; N, 9.45 Reference Example 40 N- (2-allylthio-5) -Trifluoromethylphenyl) -N'-tert-butylurea (0.6 g) in chloroform (15 ml) solution under ice-cooling m-chloroperbenzoic acid (content
A solution of 80% (0.39 g) in chloroform (6 ml) was added dropwise.
The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and then dried. The solvent was distilled off, and the residue was purified by column chromatography [silica gel (30 g), eluted with ethyl acetate-hexane (1: 2)], recrystallized from isopropyl ether-hexane, and purified to give 20 (allylsulfinyl-5-trifluoro). Colorless needles of (methylphenyl) -N'-tert-butylurea were obtained. Yield 0.59 g (94.0%). mp.113-11
4 ° C.
元素分析値C15H19F3N2O2Sとして 計算値:C,51.71;H,5.50;N,8.04 実測値:C,51.75;H,5.55;N,7.98 参考例41-68 参考例40と同様にして第５表の化合物を得た。Elemental analysis: C 15 H 19 F 3 N 2 O 2 S Calculated: C, 51.71; H, 5.50; N, 8.04 Found: C, 51.75; H, 5.55; N, 7.98 Reference Examples 41-68 Reference Examples 41-68 Compounds in Table 5 were obtained in the same manner as in 40.
参考例75 ２−アリルチオ安息香酸（9.2g）のTHF（50ml）溶液
に、塩化オキサリル（7.2g）を加え、さらにDMF（1dro
p）を加えて室温で２時間かきまぜた。溶媒を留去し残
留物をアセトン（15ml）に溶かし、ナトリウムアジド
（4.6g）の水（15ml）溶液に13〜15℃で滴下した。１時
間かきまぜた後、ベンゼン（20ml×３）で抽出した。ベ
ンゼン抽出層は水洗、乾燥（MgSO4）後、65℃で１時間
かきまぜた。溶媒を留去し、残留物を減圧蒸留に付し２
−アリルチオフェニルイソシアナートを無色油状物（7.
2g,80％）として得た。bp98℃/0.7mmHg NMR（δ ppm in CDCl3）:3.88（2H,d,J＝7.5Hz）,4.85
〜5.15（2H,m）,5.6〜6.1（1H,m）,6.9〜7.5（4H,m） IR（neat）:2270,2220,1580,1500,920,755（cm-1） 参考例76 ２−アリルチオフェニルイソシアナート（0.96g）お
よびジエチルｐ−アミノベンジルホスホネート（1.2g）
をトルエン（5ml）に溶かし30分間還流下に加熱した。
反応混合物を氷冷し、ヘキサンを加え折出結晶をろ取し
た。酢酸エチルから再結晶し、ジエチル４−［３−（２
−アリルチオフェニル）ウレイド］ベンジルホスホネー
ト（2.0g,91％）を無色プリズム晶として得た。 Reference Example 75 Oxalyl chloride (7.2 g) was added to a solution of 2-allylthiobenzoic acid (9.2 g) in THF (50 ml), and DMF (1 dro
p) was added and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, the residue was dissolved in acetone (15 ml), and added dropwise to a solution of sodium azide (4.6 g) in water (15 ml) at 13 to 15 ° C. After stirring for 1 hour, the mixture was extracted with benzene (20 ml × 3). The benzene extract layer was washed with water, dried (MgSO 4 ) and stirred at 65 ° C. for 1 hour. The solvent was distilled off and the residue was subjected to vacuum distillation.
-Allylthiophenyl isocyanate was converted to a colorless oil (7.
2g, 80%). bp 98 ° C./0.7 mmHg NMR (δ ppm in CDCl 3 ): 3.88 (2H, d, J = 7.5 Hz), 4.85
-5.15 (2H, m), 5.6-6.1 (1H, m), 6.9-7.5 (4H, m) IR (neat): 2270,2220,1580,1500,920,755 (cm -1 ) Reference example 76 2-ant Luthiophenyl isocyanate (0.96 g) and diethyl p-aminobenzylphosphonate (1.2 g)
Was dissolved in toluene (5 ml) and heated under reflux for 30 minutes.
The reaction mixture was ice-cooled, hexane was added, and the precipitated crystals were collected by filtration. Recrystallization from ethyl acetate gave diethyl 4- [3- (2
-Allylthiophenyl) ureido] benzylphosphonate (2.0 g, 91%) as colorless prisms.
mp117-118℃ 元素分析値C21H27N2O4PSとして 計算値:C,58.05;H,6.26;N,6.45 実測値:C,57.94;H,6.23;N,6.61 参考例77 参考例74と同様にしてジエチル４−［３−（２−アリ
ルチオフェニル）ウレイド］フェニルホスホネートを得
た。収率83％。mp133-134℃（酢酸エチル−ヘキサン） 元素分析値C20H25N2O4PSとして 計算値:C,57.13;H,5.99;N,6.66 実測値:C,57.25;H,5.96;N,6.52 実施例１ Ａ法:N−（２−アリルスルフィニル−３−クロフェニ
ル）−Ｎ′−メチルウレア（1.93g）,4−ジメチルアミ
ノピリジン（0.86g），クロロホルム（20ml）の混合物
を13.5時間加熱還流した。反応混合物を濃縮し、残留物
をカラムクロマトグラフィー［担体：シリカゲル100g、
酢酸エチル−ヘキサン（1:2）溶出］で精製し、８−ク
ロロ−２−メチル−1,2,4−ベンゾチアジアジン−３（4
H）−オンの結晶を得た。酢酸エチル−ヘキサンから再
結晶。無色針状晶。mp.165-166℃。収量1.03g（収率67.
8％）。mp117-118 ° C Elemental analysis: C 21 H 27 N 2 O 4 PS Calculated: C, 58.05; H, 6.26; N, 6.45 Found: C, 57.94; H, 6.23; N, 6.61 Reference example 77 Reference example In the same manner as in 74, diethyl 4- [3- (2-allylthiophenyl) ureido] phenylphosphonate was obtained. 83% yield. mp 133-134 ° C (ethyl acetate-hexane) Elemental analysis: C 20 H 25 N 2 O 4 PS Calculated: C, 57.13; H, 5.99; N, 6.66 Found: C, 57.25; H, 5.96; N, 6.52 Example 1 Method A: Heat a mixture of N- (2-allylsulfinyl-3-clophenyl) -N'-methylurea (1.93 g), 4-dimethylaminopyridine (0.86 g) and chloroform (20 ml) for 13.5 hours Refluxed. The reaction mixture is concentrated, and the residue is subjected to column chromatography [carrier: 100 g of silica gel,
Elution with ethyl acetate-hexane (1: 2)] to give 8-chloro-2-methyl-1,2,4-benzothiadiazine-3 (4
H) -one crystals were obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. mp.165-166 ° C. Yield 1.03 g (67.
8%).
元素分析値C8H7ClN2OSとして 計算値:C,44.76;H,3.29;N,13.05 実測値:C,44.75;H,3.21;N,13.19 実施例２ Ｂ法 ６−トリフルオロメチル−1,2,4−ベンゾチアジ
アジン−３（4H）−オン（1.17g）のN,N−ジメチルホル
ムアミド（DMF）（6ml）溶液に氷冷下、油性水素化ナト
リウム（60％,0.2g）を加え10分間かきまぜた。ついで
２−ブロモエチルベンゼン（0.92g）を加え、室温で5.5
時間かきまぜ、反応液を水に注いで酢酸エチルで抽出し
た。酢酸エチル層を、水洗、乾燥（MgSO4）後溶媒を留
去した。残留物をシリカゲルカラムクロマトグラフィー
［酢酸エチル−ヘキサン（1:2）溶出］で精製し２−フ
ェネチル−６−トリフルオロメチル−1,2,4−ベンゾチ
アジアジン−３（4H）−オンの結晶を得た。イソプロピ
ルエーテル−ヘキサンから再結晶した。無色板状晶。m
p.152-153℃。収量838mg（49.6％）。Elemental analysis: as C 8 H 7 ClN 2 OS Calculated: C, 44.76; H, 3.29; N, 13.05 Found: C, 44.75; H, 3.21; N, 13.19 Example 2 Method B 6-trifluoromethyl- Oily sodium hydride (60%, 0.2 g) was added to a solution of 1,2,4-benzothiadiazin-3 (4H) -one (1.17 g) in N, N-dimethylformamide (DMF) (6 ml) under ice cooling. ) And stirred for 10 minutes. Then, 2-bromoethylbenzene (0.92 g) was added, and the mixture was added at room temperature for 5.5 minutes.
After stirring for an hour, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO 4 ), and the solvent was distilled off. The residue was purified by silica gel column chromatography [ethyl acetate-hexane (1: 2) elution] to give 2-phenethyl-6-trifluoromethyl-1,2,4-benzothiadiazin-3 (4H) -one. Crystals were obtained. Recrystallized from isopropyl ether-hexane. Colorless platelets. m
p. 152-153 ° C. Yield 838mg (49.6%).
元素分析値C16H13F3N2OSとして 計算値:C,56.80;H,3.87;N,8.28 実測値:C,56.72;H,3.87;N,8.26 実施例３〜41 実施例1,2と同様にして第６表の化合物を得た。Elemental analysis value as C 16 H 13 F 3 N 2 OS Calculated value: C, 56.80; H, 3.87; N, 8.28 Actual value: C, 56.72; H, 3.87; N, 8.26 Examples 3 to 41 In the same manner as in 2, the compounds shown in Table 6 were obtained.
実施例58 錠剤 １錠中の組成 （１）化合物Ａ（実施例１で得られた化合物） 50mg （２）コーンスターチ 30mg （３）乳糖 113.4mg （４）ヒドロキシプロピルセルロース 6mg （５）水 （0.03ml）（６）ステアリン酸マグネシウム 0.6mg 計 200mg 上記の組成のうち、（１），（２），（３）及び
（４）を混合し、それに水を加え練合を行った後、40
℃,16時間真空乾燥し、乳鉢で粉砕し、16メッシュの篩
を通して顆粒とした。この顆粒に（６）を加え混合し、
ロータリー式打錠機（菊水製作所製）で１錠あたり200m
gの錠剤を製造した。 Example 58 Tablet Composition in One Tablet (1) Compound A (compound obtained in Example 1) 50 mg (2) Corn starch 30 mg (3) Lactose 113.4 mg (4) Hydroxypropylcellulose 6 mg (5) Water (0.03 ml) (6) Magnesium stearate 0.6 mg Total 200 mg Of the above composition, mix (1), (2), (3) and (4), add water and knead,
C., vacuum dried for 16 hours, crushed in a mortar, and passed through a 16-mesh sieve to obtain granules. (6) is added to the granules and mixed,
200m per tablet with a rotary tableting machine (manufactured by Kikusui Seisakusho)
g tablets were produced.
実施例59 （１）化合物Ｂ（実施例23で得られた化合物） 50mg （２）コーンスターチ 30mg （３）乳糖 113.4mg （４）ヒドロキシセルロース 6mg （５）水 （0.03ml） （６）ステアリン酸マグネシウム 0.6mg （７）セルロースアセテートフタレート 10mg（８）アセトン （0.2ml） 計 210mg 上記の組成のうち、（１）、（２）、（３）、４）、
（５）及び（６）を用い実施例42と同様にして錠剤を製
造した。この錠剤に（７）のアセトン溶液をハーコータ
ー（フロイント社製）でフィルムコートし、１錠あたり
210mgの腸溶剤を製造した。Example 59 (1) Compound B (the compound obtained in Example 23) 50 mg (2) Corn starch 30 mg (3) Lactose 113.4 mg (4) Hydroxycellulose 6 mg (5) Water (0.03 ml) (6) Magnesium stearate 0.6mg (7) Cellulose acetate phthalate 10mg (8) Acetone (0.2ml) total 210mg Of the above composition, (1), (2), (3), 4),
Tablets were produced in the same manner as in Example 42 using (5) and (6). This tablet was film-coated with the acetone solution of (7) using a har coater (manufactured by Freund).
210 mg enteric solvent was produced.
実施例60 カプセル中の組成 （１）化合物Ｃ（実施例20で得られた化合物） 30mg （２）コーンスターチ 40mg （３）乳糖 74mg （４）ヒドロキシセルロース 6mg（５）水 （0.02ml） 計 150mg 上記の組成のうち、（１），（２），（３）及び
（４）を混合し、それに水を加え練合を行った後、40
℃、16時間真空乾燥し乳鉢で粉砕し、16メッシュの篩を
通して顆粒とした。この顆粒をカプセル充填機（イタリ
ア、ザナシー社製）でゼラチン３号カプセルに充填し、
カプセル剤を製造した。Example 60 Composition in Capsule (1) Compound C (Compound obtained in Example 20) 30 mg (2) Corn starch 40 mg (3) Lactose 74 mg (4) Hydroxycellulose 6 mg (5) Water (0.02 ml) 150 mg in total After mixing (1), (2), (3) and (4) in the composition of the above, adding water thereto and kneading,
C. for 16 hours under vacuum, pulverized in a mortar, and passed through a 16-mesh sieve to obtain granules. These granules are filled into gelatin No. 3 capsules with a capsule filling machine (manufactured by Xanasea, Italy)
A capsule was produced.
実施例61 （１）化合物Ｄ（実施例11で得られた化合物） 5mg （２）サリチル酸ナトリウム 50mg （３）塩化ナトリウム 180mg （４）メタ重亜硫酸ナトリウム 20mg （５）メチル−パラベン 36mg （６）プロピル−パラベン 4mg（７）注射用蒸留水 （2.0ml） 計 295mg 上記の組成のうち、（２）、（３）、（４）、（５）
及び（６）を撹拌しながら80℃で上記の約半分の蒸留水
に溶解する。得られた溶液を40℃まで冷却し、化合物
（Ｄ）をその溶液中に溶解する。次にその溶液に注射用
蒸留水を加えて最終の容量に調整し、滅菌フィルター
（デラポア，ミリポアフィルター社製）を用いて滅菌ろ
過して、注射剤を調製した。Example 61 (1) Compound D (compound obtained in Example 11) 5 mg (2) Sodium salicylate 50 mg (3) Sodium chloride 180 mg (4) Sodium metabisulfite 20 mg (5) Methyl-paraben 36 mg (6) Propyl -Paraben 4mg (7) Distilled water for injection (2.0ml) Total 295mg Of the above composition, (2), (3), (4), (5)
And (6) are dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the compound (D) is dissolved in the solution. Next, distilled water for injection was added to the solution to adjust the final volume, and the solution was sterilized and filtered using a sterile filter (Delapore, manufactured by Millipore Filter Co.) to prepare an injection.
発明の効果 本発明の化合物（Ｉ）は、すぐれた骨吸収抑制作用を
有するので、哺乳動物の骨粗鬆症予防治療剤として有用
である。Effect of the Invention Since the compound (I) of the present invention has an excellent bone resorption inhibiting action, it is useful as an agent for preventing and treating osteoporosis in mammals.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 // Ｃ０７Ｄ 417/06 ２１３ Ｃ０７Ｄ 417/06 ２１３ 471/04 １１８ 471/04 １１８Ｚ ──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. 6 Identification number Agency reference number FI Technical display location // C07D 417/06 213 C07D 417/06 213 471/04 118 471/04 118Z
Claims (4)
ン原子，置換されていてもよい低級アルキル，置換され
ていてもよい水酸基，または低級アシルを示すか、ある
いは隣接するR1とR2とが互いに連結して式−（CH2）ｍ
−（式中、ｍは３〜５の整数を示す）または式−Ｏ−
（CH2）ｎ−Ｏ−（式中、ｎは１〜３の整数を示す）で
表される環を形成することを示し、R3は水素，低級アル
キルあるいはアラルキルを、R4は水素またはそれぞれ置
換されていてもよいアルキル，アラルキル，アルケニ
ル，芳香族あるいは複素環基を示す］で表される化合物
またはその塩を含有してなる骨粗鬆症予防治療剤。(1) General formula [Wherein, R 1 and R 2 are the same or different and each represent hydrogen, a halogen atom, an optionally substituted lower alkyl, an optionally substituted hydroxyl group, or a lower acyl, or two adjacent R 1 and R 2 And 2 are linked to each other to form the formula-(CH 2 ) m
-(Wherein, m represents an integer of 3 to 5) or -O-
(CH 2 ) n—O— (wherein n represents an integer of 1 to 3), R 3 represents hydrogen, lower alkyl or aralkyl, R 4 represents hydrogen or Or a substituted or unsubstituted alkyl, aralkyl, alkenyl, aromatic or heterocyclic group] or a salt thereof.
素、（ii）ハロゲン原子、（iii）ハロゲン原子，水酸
基およびC1-6アルコキシから選択される１〜３個の置換
基を有していてもよいC1-6アルキル、（iv）水酸基，C
1-6アルコキシ，フェニル−C1-4アルキルオキシまたはC
2-4アルカノイルオキシ、または（ｖ）ホルミルまたはC
1-6アルキル−カルボニルであるか、あるいは隣接するR
1とR2とが互いに連結して式−（CH2）ｍ−（式中、ｍは
３または４を示す）または式−Ｏ−（CH2）ｎ−Ｏ−
（式中、ｎは１または２を示す）で表される環を形成す
る、 R3が水素，C1-6アルキルまたはフェニル−C1-4アルキル
で、 R4が（ｉ）水素、（ii）ハロゲン，水酸基，C1-6
アルコキシ，C1-6アルキル，C1-10アシルで置換さ
れていてもよいアミノ，C1-6アルキルで置換されてい
てもよいカルバモイル，C1-6アルコキシ−カルボニル
または２−ピリジル,3−ピリジル,4−ピリジル，ピリ
ミジル，ピラジニル，ピリダジニル，ピラゾリル，イミ
ダゾリル、チアゾリル，イソチアゾリル，オキサゾリ
ル，イソオキサゾリル，ピリド［2,3−ｄ］ピリミジ
ル，ベンゾピラニル,1,8−ナフチリジル,1,5−ナフチリ
ジル,1,6−ナフチリジル,1,7−ナフチリジル,2,7−ナフ
チリジル,2,6−ナフチリジル，キノリル，チエノ［2,3
−ｂ］ピリジル，テトラゾリル，チアジアゾリル，オキ
サジアゾリル，トリアジニル，チエニル，ピロリル，ピ
ロリニル，フリル，ピロリジニル，ベンゾチエニル，イ
ンドリル，イミダゾリジニル，ピペリジル，ピペリジニ
ノ，ピペラジニル，モルホリニルおよびモルホリノから
選択される複素環で、置換されていてもよい直鎖，分枝
または環状C1-10アルキル、（iii）ハロゲン，C1-6
アルコキシ，C1-6アルキル，ハロゲン化C1-6アルキ
ル，C1-6アルキルもしくはC1-10アシルで置換されて
いてもよいアミノ，C1-6アルコキシで置換されていて
もよいホスホリルもしくはホスホリルC1-6アルキルまた
はハロゲンで置換されていてもよいC6-14アリール
で、置換されていてもよいフェニル−C1-4アルキル，
（iv）ハロゲン，水酸基，C1-6アルコキシ，C1-6
アルキル，C1-10アシルで置換されていてもよいアミ
ノ，C1-6アルキルで置換されていてもよいカルバモイ
ル，C1-6アルコキシ−カルボニルまたは２−ピリジ
ル,3−ピリジル,4−ピリジル，ピリミジル，ピラジニ
ル，ピリダジニル，ピラゾリル，イミダゾリル，チアゾ
リル，イソチアゾリル，オキサゾリル，イソオキサゾリ
ル，ピリド［2,3−ｄ］ピリミジル，ベンゾピラニル,1,
8−ナフチリジル,1,5−ナフチリジル,1,6−ナフチリジ
ル,1,7−ナフチリジル,2,7−ナフチリジル,2,6−ナフチ
リジル，キノリル，チエノ［2,3−ｂ］ピリジル，テト
ラゾリル，チアジアゾリル，オキサジアゾリル，トリア
ジニル，チエニル，ピロリル，ピロリニル，フリル，ピ
ロリジニル，ベンゾチエニル，インドリル，イミダゾリ
ジニル，ピペリジル，ピペリジノ，ピペラジニル，モル
ホリニルおよびモルホリノから選択される複素環で、置
換されていてもよいC2-6アルケニル，（ｖ）ハロゲ
ン，C1-6アルコキシ，C1-6アルキル，ハロゲン化
C1-6アルキル，C1-6アルキルもしくはC1-10アシルで
置換されていてもよいアミノ，C1-6アルコキシで置換
されていてもよいホスホリルもしくはホスホリルC1-6ア
ルキルまたはハロゲンで置換されていてもよいC6-14
アリールで、置換されていてもよいC6-14アリールまた
は（vi）ハロゲン，C1-6アルコキシ，C1-6アルキ
ル，ハロゲン化C1-6アルキル，C1-6アルキルもしく
はC1-10アシルで置換されていてもよいアミノ，C1-6
アルコキシで置換されていてもよいホスホリルもしくは
ホスホリルC1-6アルキルまたはハロゲンで置換されて
いてもよいC6-14アリールで、置換されていてもよい２
−ピリジル,3−ピリジル,4−ピリジル，ピリミジル，ピ
ラジニル，ピリダジニル，ピラゾリル，イミダゾリル，
チアゾリル，イソチアゾリル，オキサゾリル，イソオキ
サゾリル，ピリド［2,3−ｄ］ピリミジル，ベンゾピラ
ニル,1,8−ナフチリジル,1,5−ナフチリジル,1,6−ナフ
チリジル,1,7−ナフチリジル,2,7−ナフチリジル,2,6−
ナフチリジル，キノリル，チエノ［2,3−ｂ］ピリジ
ル，テトラゾリル，チアジアゾリル，オキサジアゾリ
ル，トリアジニル，チエニル，ピロリル，ピロリニル，
フリル，ピロリジニル，ベンゾチエニル，インドリル，
イミダゾリジニル，ピペリジル，ピペリジノ，ピペラジ
ニル，モルホリニルおよびモルホリノから選択される複
素環である、請求項１記載の骨粗鬆症予防治療剤。2. R 1 and R 2 are the same or different and each has 1 to 3 substituents selected from (i) hydrogen, (ii) halogen atom, (iii) halogen atom, hydroxyl group and C 1-6 alkoxy. C 1-6 alkyl optionally having (iv) a hydroxyl group, C
1-6 alkoxy, phenyl-C 1-4 alkyloxy or C
2-4 alkanoyloxy, or (v) formyl or C
1-6 alkyl-carbonyl or adjacent R
1 and R 2 are linked to each other to form a group represented by the formula-(CH 2 ) m- (where m represents 3 or 4) or a group represented by the formula -O- (CH 2 ) n-O-
Wherein n represents 1 or 2, R 3 is hydrogen, C 1-6 alkyl or phenyl-C 1-4 alkyl, R 4 is (i) hydrogen, ( ii) Halogen, hydroxyl group, C 1-6
Alkoxy, C 1-6 alkyl, amino optionally substituted with C 1-10 acyl, carbamoyl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy-carbonyl or 2-pyridyl, 3- Pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido [2,3-d] pyrimidyl, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1, 6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl, thieno [2,3
-B] substituted with a heterocycle selected from pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidinino, piperazinyl, morpholinyl and morpholino. Linear, branched or cyclic C 1-10 alkyl, (iii) halogen, C 1-6
Amino optionally substituted by alkoxy, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkyl or C 1-10 acyl, phosphoryl optionally substituted by C 1-6 alkoxy or Phosphoryl C 1-6 alkyl or C 6-14 aryl optionally substituted with halogen, and optionally substituted phenyl-C 1-4 alkyl,
(Iv) halogen, hydroxyl group, C 1-6 alkoxy, C 1-6
Alkyl, amino optionally substituted with C 1-10 acyl, carbamoyl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy-carbonyl or 2-pyridyl, 3-pyridyl, 4-pyridyl, Pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido [2,3-d] pyrimidyl, benzopyranyl, 1,
8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl, thieno [2,3-b] pyridyl, tetrazolyl, thiadiazolyl, Optionally substituted C 2-6 alkenyl with a heterocycle selected from oxadiazolyl, triazinyl, thienyl, pyrrolyl, pyrrolyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl and morpholino; (V) halogen, C 1-6 alkoxy, C 1-6 alkyl, halogenated
C 1-6 alkyl, substituted by C 1-6 alkyl or C 1-10 acyl amino optionally substituted, C 1-6 optionally phosphoryl optionally substituted by alkoxy or phosphoryl C 1-6 alkyl or halogen C 6-14 which may be
Aryl, optionally substituted C 6-14 aryl or (vi) halogen, C 1-6 alkoxy, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkyl or C 1-10 Amino optionally substituted with acyl, C 1-6
Optionally substituted with phosphoryl or phosphoryl C 1-6 alkyl optionally substituted with alkoxy or C 6-14 aryl optionally substituted with halogen
-Pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl,
Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido [2,3-d] pyrimidyl, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-
Naphthyridyl, quinolyl, thieno [2,3-b] pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, thienyl, pyrrolyl, pyrrolinyl,
Furyl, pyrrolidinyl, benzothienyl, indolyl,
The preventive or therapeutic agent for osteoporosis according to claim 1, which is a heterocyclic ring selected from imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl and morpholino.
ン原子，置換されていてもよい低級アルキル，置換され
ていてもよい水酸基，または低級アシルを示すか、ある
いは隣接するR1とR2とが互いに連結して式−（CH2）ｍ
−（式中、ｍは３〜５の整数を示す）または式−Ｏ−
（CH2）ｎ−Ｏ−（式中、ｎは１〜３の整数を示す）で
表される環を形成することを示し、R3は水素，低級アル
キルあるいはアラルキルを、R4″はメチル，エチルまた
はベンジルを示す。ただし、R1，R2およびR3は同時に水
素ではない］で表される化合物またはその塩。3. The general formula [Wherein, R 1 and R 2 are the same or different and each represent hydrogen, a halogen atom, an optionally substituted lower alkyl, an optionally substituted hydroxyl group, or a lower acyl, or two adjacent R 1 and R 2 And 2 are linked to each other to form the formula-(CH 2 ) m
-(Wherein, m represents an integer of 3 to 5) or -O-
(CH 2 ) n—O— (wherein n represents an integer of 1 to 3), R 3 represents hydrogen, lower alkyl or aralkyl, and R 4 ″ represents methyl , Ethyl or benzyl, provided that R 1 , R 2 and R 3 are not hydrogen at the same time].
素、（ii）ハロゲン原子、（iii）ハロゲン原子，水酸
基およびC1-6アルコキシから選択される１〜３個の置換
基を有していてもよいC1-6アルキル、（iv）水酸基，C
1-6アルコキシ，フェニル−C1-4アルキルオキシまたはC
2-4アルカノイルオキシ、または（ｖ）ホルミルまたはC
1-6アルキル−カルボニルであるか、あるいは隣接するR
1とR2とが互いに連結して式−（CH2）ｍ−（式中、ｍは
３または４を示す）または式−Ｏ−（CH2）ｎ−Ｏ−
（式中、ｎは１または２を示す）で表される環を形成す
る、R3が水素，C1-6アルキルまたはフェニル−C1-4アル
キルである請求項３記載の化合物またはその塩。4. A method wherein R 1 and R 2 are the same or different and each has 1 to 3 substituents selected from (i) hydrogen, (ii) halogen atom, (iii) halogen atom, hydroxyl group and C 1-6 alkoxy. C 1-6 alkyl optionally having (iv) a hydroxyl group, C
1-6 alkoxy, phenyl-C 1-4 alkyloxy or C
2-4 alkanoyloxy, or (v) formyl or C
1-6 alkyl-carbonyl or adjacent R
1 and R 2 are linked to each other to form a group represented by the formula-(CH 2 ) m- (where m represents 3 or 4) or a group represented by the formula -O- (CH 2 ) n-O-
4. The compound according to claim 3 , wherein R 3 is hydrogen, C 1-6 alkyl or phenyl-C 1-4 alkyl, which forms a ring represented by the formula (where n represents 1 or 2) or a salt thereof. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63318750A JP2724396B2 (en) | 1987-12-18 | 1988-12-16 | Osteoporosis prevention and treatment agent |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62-322348 | 1987-12-18 | ||
| JP32234887 | 1987-12-18 | ||
| JP63318750A JP2724396B2 (en) | 1987-12-18 | 1988-12-16 | Osteoporosis prevention and treatment agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01238529A JPH01238529A (en) | 1989-09-22 |
| JP2724396B2 true JP2724396B2 (en) | 1998-03-09 |
Family
ID=26569495
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63318750A Expired - Lifetime JP2724396B2 (en) | 1987-12-18 | 1988-12-16 | Osteoporosis prevention and treatment agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2724396B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6008208A (en) | 1995-10-23 | 1999-12-28 | Osteoscreen, Inc. | Compositions and methods for treating bone deficit conditions |
| AU706262B2 (en) * | 1995-10-23 | 1999-06-10 | Osteoscreen, Inc. | Compositions and methods for treating bone deficit conditions |
-
1988
- 1988-12-16 JP JP63318750A patent/JP2724396B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01238529A (en) | 1989-09-22 |
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