JPH0395117A - Metabolic bone disease therapeutic agent - Google Patents
Metabolic bone disease therapeutic agentInfo
- Publication number
- JPH0395117A JPH0395117A JP15017290A JP15017290A JPH0395117A JP H0395117 A JPH0395117 A JP H0395117A JP 15017290 A JP15017290 A JP 15017290A JP 15017290 A JP15017290 A JP 15017290A JP H0395117 A JPH0395117 A JP H0395117A
- Authority
- JP
- Japan
- Prior art keywords
- group
- therapeutic agent
- active ingredient
- metabolic bone
- tetrahydroquinoline
- 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.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 19
- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 17
- 208000029725 Metabolic bone disease Diseases 0.000 title claims abstract description 14
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- -1 cyclic anthranilic acid derivative Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 239000004480 active ingredient Substances 0.000 claims abstract 11
- 150000001447 alkali salts Chemical class 0.000 claims abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 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
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- RQKKMIGVKYFMGF-UHFFFAOYSA-N 2-(4-propan-2-yloxyphenyl)-1,2,3,4-tetrahydroquinoline-8-carboxylic acid Chemical group C1=CC(OC(C)C)=CC=C1C1NC2=C(C(O)=O)C=CC=C2CC1 RQKKMIGVKYFMGF-UHFFFAOYSA-N 0.000 claims 1
- JPNDKTYCJLRQIC-UHFFFAOYSA-N 6-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline-8-carboxylic acid Chemical group N1C=2C(C(=O)O)=CC(Cl)=CC=2CCC1C1=CC=CC=C1 JPNDKTYCJLRQIC-UHFFFAOYSA-N 0.000 claims 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000012634 fragment Substances 0.000 description 10
- 230000024279 bone resorption Effects 0.000 description 9
- 208000006386 Bone Resorption Diseases 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- PLTGFWDGFXPMCJ-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline-8-carboxylic acid Chemical compound C1CCNC2=C1C=CC=C2C(=O)O PLTGFWDGFXPMCJ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZXTHWIZHGLNEPG-UHFFFAOYSA-N 2-phenyl-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC=C1 ZXTHWIZHGLNEPG-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical compound C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 229940037448 calcitonin preparations Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 201000008972 osteitis fibrosa Diseases 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
〔産業上の利川分野〕
本発明は、骨吸収抑制作用を持ち、骨代謝疾患に対する
治療効果を有する環状アントラニル酸誘導体、それ等の
酸付加塩又はアルツｌり塩及びそれらを有効成分とする
骨代謝疾患治療剤に関する
〔従来の技術〕
代謝性骨疾患とは、骨粗壓症，骨軟化症，線維性骨炎な
どの総称であり、全身の骨形成及び骨吸収の過程に破綻
が生じ、骨質量，骨の組成．骨の構造が病的に変化した
ものである。各種のホルモン．ビタミンなどの生態内調
節機構の異常．先天性又は後天ｉ４、の骨細胞の異常な
働きにより生じ、カルシウムとリンの代謝異常をｆ゛｛
くう。Detailed Description of the Invention [Industrial field in Icheon] The present invention provides cyclic anthranilic acid derivatives, their acid addition salts or alzyl salts, and [Prior art] Metabolic bone disease is a general term for osteoporosis, osteomalacia, osteitis fibrosa, etc., and is a disease that affects bone formation and resorption throughout the body. A breakdown occurs in the process of bone mass and bone composition. This is a pathological change in bone structure. Various hormones. Abnormalities in biological regulatory mechanisms such as vitamins. It is caused by the abnormal function of bone cells, either congenital or acquired, and causes metabolic abnormalities of calcium and phosphorus.
eat.
その治療剤としてはビタミンＤ製剤，カルシウム製剤，
カルシトニン製剤，リン製剤等が用いられるが、その効
果は確実ではなく、より優れた薬物の開発が強く望まれ
ている。Therapeutic agents include vitamin D preparations, calcium preparations,
Calcitonin preparations, phosphorus preparations, etc. are used, but their effectiveness is not certain, and the development of better drugs is strongly desired.
また、３−フェニル−−４Ｈ−１−ペンゾピラン−４−
オン誘導体（イブリフラポン），更に２−フェニル−４
Ｈ−１−ペンゾピラン−４−オン誘導体等が、骨吸収抑
制作用を有し、骨粗表の治療薬として有川であることか
報告されている。しかし、その作用は弱く、骨代謝疾患
の治療薬としては決して満足できるものではなかった。Also, 3-phenyl--4H-1-penzopyran-4-
ion derivative (Ibriflapon), and also 2-phenyl-4
It has been reported that H-1-penzopyran-4-one derivatives and the like have a bone resorption inhibitory effect and are effective as therapeutic agents for osteoporosis. However, its effect was weak, and it was by no means satisfactory as a therapeutic agent for bone metabolic diseases.
本出頭人は、先に一般式［Ｉ１で表される環状アントラ
ニル酸誘導体、それらの酸付加塩又はアルカリ境が免疫
調節作用及び強力な抑制ヤＬＴ細胞の誘導能を有し、か
つリウマチ姓関節炎に対して治療効果を有することを見
出し、特願昭６３− ２３６２９５号として出願を行っ
た（特開甲１２７９８６７号）。The present applicant previously reported that cyclic anthranilic acid derivatives represented by the general formula [I1, their acid addition salts or alkaline salts, have immunomodulatory effects and the ability to induce strong suppressive and LT cells, and are associated with rheumatoid arthritis. It was discovered that it has a therapeutic effect on patients, and an application was filed as Japanese Patent Application No. 1279867-1983.
［式中Ｒ’，Ｒ２及びＲ３は同一又は相異なって水素原
子，ハロゲン原子，炭素数１〜３の低級アルキル基．炭
素数１〜３の低級アルコキシ基，アミノ基，ニトロ基，
ヒドロキシ基，スルホンアミド基，トリフルオロメチル
基，シアノ基，カルボキシル基．カルバモイル基，アセ
チル基．置換されていてもよいベンゾイルメチル基，メ
チルチオ基．置換されていてもよいフエニルエチニル基
，置換されていてもよいエチニル基，炭素数ｌ〜３の低
級アルカノイルアミノ基．置換されていてもよいペンゾ
イルアミノ基炭素数１〜３の低級アルキルスルホニルア
ミノ基又は置換されていてもよいフエニルスルホニルア
ミノ基を、Ｒ４又はＲ′は同一又はｎ１異なって水素原
子．炭素数１〜３の低級アルキル基．シアノ基，カルボ
キシル基，ヒドロキシメチル基．置換されていてもよい
フエニル基又はベンジル基をＲ６は水素原子．炭素数１
〜３の低級アルキル基又はベンジル基を、Ｘはメチレン
基，酸素原子，イオウ原子，スルフィニル基又はスルフ
ォニル基を表す］。[In the formula, R', R2 and R3 are the same or different and each represents a hydrogen atom, a halogen atom, or a lower alkyl group having 1 to 3 carbon atoms. Lower alkoxy group having 1 to 3 carbon atoms, amino group, nitro group,
Hydroxy group, sulfonamide group, trifluoromethyl group, cyano group, carboxyl group. Carbamoyl group, acetyl group. Optionally substituted benzoylmethyl group, methylthio group. An optionally substituted phenylethynyl group, an optionally substituted ethynyl group, a lower alkanoylamino group having 1 to 3 carbon atoms. An optionally substituted penzoylamino group, a lower alkylsulfonylamino group having 1 to 3 carbon atoms, or an optionally substituted phenylsulfonylamino group, where R4 or R' are the same or n1 different and each hydrogen atom. Lower alkyl group having 1 to 3 carbon atoms. Cyano group, carboxyl group, hydroxymethyl group. R6 is a hydrogen atom in an optionally substituted phenyl group or benzyl group. Carbon number 1
~3 lower alkyl group or benzyl group, and X represents a methylene group, an oxygen atom, a sulfur atom, a sulfinyl group, or a sulfonyl group].
本発明者らは、一般式［Ｉ」で表される化合物が、驚く
べきことに、強力な骨吸収抑制作用を有し、かつ安全性
が高く、骨代謝疾患治療剤として有用であることを見出
し、本発明を完ｊ戊した。The present inventors have surprisingly found that the compound represented by the general formula [I] has a strong bone resorption inhibitory effect, is highly safe, and is useful as a therapeutic agent for bone metabolic diseases. The heading completes the invention.
〔発明の効果］
以下、一般式［Ｉ］で表される化合物の中で代表的な化
合物（表１に示す）についてＹｆ用壮を裏付ける成績を
実験例によって示す。なお、これらの化合物は、特開平
１−２７９８６７号に記載の方注によって製することが
できる。[Effects of the Invention] Hereinafter, results supporting the efficacy of Yf for typical compounds (shown in Table 1) among the compounds represented by the general formula [I] will be shown using experimental examples. In addition, these compounds can be manufactured by the direct injection method described in JP-A-1-279867.
表
１
６
ＣＨ２
ＣＨ２
ＣＨ２
ＣＨ，
ＣＨ２
ＣＨ， Ｈ
Ｈ
Ｈ
Ｈ Ｐｈ
Ｈ Ｐｈ
ＨＨ
ＨＨ
Ｐｈ Ｈ
０１｛
Ｈ，ｏ’
Ｔｓ：ｐ一トルエンスルホニル
Ｐｈ：フエニル
実験例１ 骨吸収抑制作用
骨吸収測定のための放射性カルシウム
（”Ｃａ）でラベルされたマウス前腕骨片の作製はＲａ
ｉ＋＋らの方法（１． ＣＩｉｎ． ＩｎｖｅＳｔ
．， １５５１０１Ｈ＋９６５）ｊに従った。即ち、
／Ｉ父ｑ・士性塩化カルシつム（”Ｃ ａ Ｃ ｌ ２
； ２［Ｉ０μＣ ｉ ’）を妊娠１７日１１のラン
トの背部皮下にｔ．ｔ Ｑｔ Ｌ、２目後に頼動脈切断
により放血死させた。胎仔を摘出し、滅菌１） Ｂ Ｓ
で洗浄後、胎仔の前腕骨を取り出して、付着している筋
肉や両端の軟骨を取り除き、ＢＧＩｂ培地（２０％ＢＳ
Ａ含）に入れて骨片を培養した。Table 1 6 CH2 CH2 CH2 CH, CH2 CH, H H H H Ph H Ph HH HH Ph H 01{ H, o' Ts: p-Toluenesulfonyl Ph: Phenyl Experimental example 1 Bone resorption inhibitory effect For bone resorption measurement Preparation of mouse forearm bone fragments labeled with radioactive calcium (“Ca”)
The method of i++ et al. (1. CIin. InvestSt.
．． , 155101H+965)j. That is,
/I father q・calcium chloride (“C a C l 2
;2[I0μC i') was injected subcutaneously into the back of the runt on day 17 of pregnancy. t Qt L. After 2 days, the mice were exsanguinated by cutting the dependent artery. Remove the fetus and sterilize it 1) B S
After washing with
The bone fragments were cultured.
次に７ＨＩ１らの方法（１． Ｂｏｎｅ Ｍｉｎｅ『
． Ｍｅｌａｂ１， ２０？ （＋９８６）に従い、骨
吸収に対する本発明化合物の効果を測定した。方法を以
下に述べる。Next, the method of 7HI1 et al. (1. Bone Mine'
．． Melab1, 20? (+986), the effect of the present compound on bone resorption was measured. The method is described below.
骨片をミリボアフィルター上に乗せ、０．６ｍｌのＢＧ
Ｊｂ培地（２０％ＢＳ人含）を入れた２４穴プレートウ
エル中、３７゜Ｃ， ５％二酸化炭素下で前培養した
。２４時間の前培養後、インターロイキン−１β（ＩＬ
−１β）又はＩＬ−１βと薬物を添加した試験培地へ骨
をフィルターごと移し、培養を続けた。試験培地で７２
時間培養後、上ｉＨ．３ｍｌを採取し、骨片から枚出さ
れた”Ｃ ａの測定を行った。骨片は０．３ｍｌのｌ規
定塩酸に１．５時間以上浸した後、ＩＯｍｌのＡＣＳＴ
Ｉを加えて枚射活外を測定した。なお、骨吸収の活性は
、骨片に含まれていた全放射活性（骨片と培養上清の放
射活外のｆ１］）に占める培養上清に放出された４′Ｃ
ａの割合（百分串）で表した。一つの骨片に対し、２４
穴プレートの１ウエルを使用し、との実験群も１匹の妊
娠ラットから得られた胎仔の５−６個の骨片で構成した
。Place the bone fragments on a millibore filter and add 0.6 ml of BG.
The cells were precultured in 24-well plate wells containing Jb medium (containing 20% BS) at 37°C under 5% carbon dioxide. After 24 hours of preincubation, interleukin-1β (IL
The bones were transferred together with the filter to a test medium supplemented with IL-1β) or IL-1β and drugs, and culture was continued. 72 in test medium
After incubation for an hour, the upper iH. 3 ml of bone fragments was collected and the ``Ca'' extracted from the bone fragments was measured.The bone fragments were immersed in 0.3 ml of normal hydrochloric acid for over 1.5 hours, and then soaked in IO ml of ACST.
I was added to measure the out-of-sheet activity. The bone resorption activity is determined by the 4'C released into the culture supernatant, which accounts for the total radioactivity contained in bone fragments (f1 excluding the radioactivity of bone fragments and culture supernatant]).
Expressed as a percentage of a (percentage scale). 24 for one bone fragment
One well of the well plate was used, and the experimental groups also consisted of 5-6 bone fragments of fetuses obtained from one pregnant rat.
骨吸収抑制率（％）は次式によった。The bone resorption inhibition rate (%) was calculated by the following formula.
結果を表２に示す
表
２
以上のように、一般式［ＩＪで表される本発明化合物は
、強力な骨吸収抑制作用を有し、代謝性骨疾患治療剤と
して有用である。The results are shown in Table 2 As described above, the compound of the present invention represented by the general formula [IJ] has a strong bone resorption inhibitory effect and is useful as a therapeutic agent for metabolic bone diseases.
次に本発明の実験例に供した化合物につ０て合戊例を以
下に述べる。Next, a synthesis example will be described below regarding the compounds used in the experimental examples of the present invention.
参考例１
５，６−ジヒドロー４Ｈ−ピロロ［３． ２． Ｉ−ｉ
ｉｌキノリン１２−ジオン
オキザリルクロライド２２…１を乾燥テトラヒドロフラ
ン（ＴＨＦ） ＩｏＯｍｌに加え、還流下、ｌ， ２．
３４−テトラヒドロキノリンｌＬ５ｇを乾燥ＴＩＩＦ
＋５（１ｍｌに溶解した溶液を滴下した。滴下後３．
５時間還流した。冷却後、濃縮して得られた残漬に二硫
化炭素８ＱＯｍｌを加え、よく撹拌下還流した。Reference Example 1 5,6-dihydro 4H-pyrrolo [3. 2. I-i
il quinoline 12-dione oxalyl chloride 22...1 was added to 100 ml of dry tetrahydrofuran (THF) under reflux.
Dry 5 g of 34-tetrahydroquinoline in TIIF
+5 (a solution dissolved in 1 ml was added dropwise. After dropping 3.
It was refluxed for 5 hours. After cooling, 8 QOml of carbon disulfide was added to the residue obtained by concentration, and the mixture was refluxed with thorough stirring.
この溶液に無水塩化アルミニウム３５ｇを２〜３ｇづつ
５時間かけて加えた。さらに３時間還流し、一晩室温に
て放置した。反応物を冷却しながら濃塩酸１５０ｍｌを
加え、さらに水１５０ｍｌを加えた。クロロホルムにて
抽出、よく水洗した後、無水硫酸ナトリウムにて乾燥、
濃縮した。得られた残渣をエタノールで再結晶し、２１
ｇ （８０％）の目的物を暗赤色針状品として得た。To this solution, 35 g of anhydrous aluminum chloride was added in 2 to 3 g portions over 5 hours. The mixture was refluxed for an additional 3 hours and left overnight at room temperature. While cooling the reaction mixture, 150 ml of concentrated hydrochloric acid was added, and further 150 ml of water was added. Extracted with chloroform, washed thoroughly with water, dried with anhydrous sodium sulfate,
Concentrated. The obtained residue was recrystallized from ethanol, and 21
g (80%) of the desired product was obtained as dark red needles.
融点１９８〜２００°Ｃ
参考例２
８−ニトロ−５，６−ジヒドロ−４Ｈ−ピロロ［３．
２． １）キノリン−１，２−シオン
発煙硝酸２０ｍｌをＯ℃に冷却し、撹拌下５，６−ジヒ
ドロ−４０−ピロロ［３． ２，ｌｉ ｉｌキノリン−
１．２−ジオン５ｇを温度があまり上昇しない程度に少
量ずつ加えた。さらに１時間撹拌後、冷蔵犀に一晩放置
した。反応液を氷水に注ぎ、結晶を冫戸取した。水洗後
、得られた結晶を加熱乾燥し、エタノールーヘキサンに
て再結晶した。３．８ｇ（６１％）の目的物を燈色桔晶
として得た。Melting point: 198-200°C Reference example 2 8-nitro-5,6-dihydro-4H-pyrrolo[3.
2. 1) Quinoline-1,2-sion 20 ml of fuming nitric acid was cooled to 0° C. and 5,6-dihydro-40-pyrrolo[3. 2, li ilquinoline-
5 g of 1,2-dione was added little by little to the extent that the temperature did not rise too much. After further stirring for 1 hour, the mixture was left in a refrigerator overnight. The reaction solution was poured into ice water, and the crystals were collected. After washing with water, the obtained crystals were dried by heating and recrystallized from ethanol-hexane. 3.8 g (61%) of the desired product was obtained as light-colored crystals.
融点１９８〜１９９℃
参考例３
８−クロロ−５．６−ジヒドロ−４−フェニル−−４１
１−ピロロ［３， ２． ｌ−ｉｉｌキノリン−１．２
−ジオン５６−ジヒドロ〜４−フェニル−ー４■−ピロ
ロ［３． ２． １〜１１１キノリン−１，２−ジオン
３．１ｇとＮ−クロロコハク酸イミドｌ．８９ｇのジメ
チルホルムアミドｆＤＸＩＦ） ５０ｍｌ溶７夜を８０
゜Ｃにて１時間撹拌した。冷却後、ＤＭＦを減圧留去し
、残渣にクロロホルム５ ０ ０ ｍｌを加え、よ《水
洗し、飽和食堆水で洗浄した。無水硫酸ナトリウムで乾
燥後、溶媒を留去し、３．４ｇ （９６．１１％）の目
的物を得た。Melting point 198-199°C Reference example 3 8-chloro-5.6-dihydro-4-phenyl-41
1-pyrrolo [3, 2. l-il quinoline-1.2
-dione 56-dihydro-4-phenyl-4■-pyrrolo [3. 2. 1-111 quinoline-1,2-dione 3.1 g and N-chlorosuccinimide l. 89g of dimethylformamide (fDXIF) dissolved in 50ml for 7 nights.
Stirred at °C for 1 hour. After cooling, DMF was distilled off under reduced pressure, and 500 ml of chloroform was added to the residue, which was then thoroughly washed with water and then with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 3.4 g (96.11%) of the desired product.
このものは、アセ１・ニトリルより再結晶して暗赤色結
品となる。This product recrystallizes from acetic acid nitrile to form a dark red crystal.
融点１７３〜１７４℃
以上の参考例と同様にして参考例４〜８化合物を合成し
た。Compounds of Reference Examples 4 to 8 were synthesized in the same manner as in Reference Examples having melting points of 173 to 174°C or higher.
再結晶溶媒
Ａ・アセトニトリル
合或例１
６−クロロ−２−フェニル−−１．２３．４−テトラヒ
ドロキノリン−８−カルボン酸
８−クロロ−５６−シヒドロー←フエニル−４８−ヒロ
ロ［３． ２，ｌｉ ｉｆキノリン−１，２−ジオン３
．４ｇと水酸化ナトリウム２ｇの水１００ｍｌ溶液に３
５％過酸化水素水５ｍｌを加え、室温にて１時間撹拌し
た。濃塩酸を加え、弱酸性とした後、析出した結晶を冫
戸取し、水洗、乾燥後３． ＩＴ ｇ （９６． ７％
）の黄色結晶を得た。このものをエタノールから再結晶
すると淡黄色針状品となる。Recrystallization Solvent A/Acetonitrile Synthesis Example 1 6-chloro-2-phenyl-1.23.4-tetrahydroquinoline-8-carboxylic acid 8-chloro-56-sihydro←phenyl-48-hydrolo[3. 2,li if quinoline-1,2-dione 3
．． 4g and 2g of sodium hydroxide in 100ml of water.
5 ml of 5% hydrogen peroxide solution was added, and the mixture was stirred at room temperature for 1 hour. After adding concentrated hydrochloric acid to make it weakly acidic, the precipitated crystals were collected, washed with water, and dried.3. IT g (96.7%
) yellow crystals were obtained. When this product is recrystallized from ethanol, it becomes pale yellow needle-like products.
融点１９９〜２００℃
元素分析値（％）： Ｃ＋６Ｈ１４ＣＩ ＮＯ２として
Ｃ ＨＮ
計算値 ６６，７９ ４，９０ ４．８７実測
値 ６６．８３ １９６ ４．８９合成例１と
同様にして表４に示した化合物を合成した。Melting point 199-200°C Elemental analysis value (%): C+6H14CI CHN as NO2 Calculated value 66,79 4,90 4.87 Actual value 66.83 196 4.89 Compound shown in Table 4 in the same manner as Synthesis Example 1 was synthesized.
合成例７
２−７エニル−６−ｐ− トルエンスルホニルアミノ１
， ２， ３． ４−テトラヒドロキノリン−８−カル
ボン酸
ａ） ２−フェニル−−６−アミノー１２３４−テトラ
ヒドロキノリン−８−カルボン酸メチルエステル
６−ニトロ−２−フェニル−−１． ２． ３． ４−
テトラヒドロキノリン−８−カルボン酸８．８０ｇをＤ
ＭＦ１００ ｍｌに溶解し、炭酸カリウム８．３ｇ，ヨ
ウ化メチル５．５ｍｌを加え、室温にて２時間撹拌した
。不溶物を冫戸去し、枦液を濃縮後、残渣に酢酸エチル
５ ０ ０ ｍｌを加え、水、飽和食塩水にて洗浄し、
無水硫酸ナトリウムで乾燥した。Synthesis Example 7 2-7enyl-6-p-toluenesulfonylamino 1
, 2, 3. 4-Tetrahydroquinoline-8-carboxylic acid a) 2-phenyl-6-amino-1234-tetrahydroquinoline-8-carboxylic acid methyl ester 6-nitro-2-phenyl-1. 2. 3. 4-
8.80 g of tetrahydroquinoline-8-carboxylic acid
It was dissolved in 100 ml of MF, 8.3 g of potassium carbonate and 5.5 ml of methyl iodide were added, and the mixture was stirred at room temperature for 2 hours. After removing the insoluble matter and concentrating the syrup, 500 ml of ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine.
It was dried with anhydrous sodium sulfate.
溶媒留去し、８．６５ｇ （９３．９％）の褐色結晶を
得た。このものをＤ■Ｆ−エタノール・ＩＩＩ ３ＱＯ
ｍｌに溶解し、１０％パラジウムー炭素１ｇを加え、水
素気流下、室温にて５時間撹拌した。触媒を冫戸去し、
冫戸液をａ縮後、６．９７ｇ （８９．３％）の目的物
を得た。The solvent was distilled off to obtain 8.65 g (93.9%) of brown crystals. This is D■F-Ethanol III 3QO
ml, 1 g of 10% palladium-carbon was added thereto, and the mixture was stirred at room temperature under a hydrogen stream for 5 hours. remove the catalyst,
After a reduction of the Chikuto liquid, 6.97 g (89.3%) of the target product was obtained.
ｂ） ２−フェニル−−６−ｐ− トルエンスルホニル
アミノー１２３．４−テトラヒドロキノリン−８−カル
ボン酸
上記化合物３．５ｇをジオキサン８０ｍｌに溶解し、ｐ
一トルエンスルホニルクロライド２．８４ｇ，トリエチ
ルアミン２．Ｉｍｌを加え、室温にて３時間撹拌した。b) 2-phenyl-6-p-toluenesulfonylamino-123.4-tetrahydroquinoline-8-carboxylic acid Dissolve 3.5 g of the above compound in 80 ml of dioxane,
2.84 g of monotoluenesulfonyl chloride, 2. triethylamine. Iml was added and stirred at room temperature for 3 hours.
反応液に水３００ｍｌを加え、酢酸エチルにて抽出し、
飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。Add 300 ml of water to the reaction solution, extract with ethyl acetate,
After washing with saturated brine, it was dried over anhydrous sodium sulfate.
溶媒留去し、４．Ｈｇの褐色結晶を得た。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；
３）にて精製し、３．７５ｇ （６９．４％）の微黄色
結晶を得た。このものをエタノール５０ｍ１に溶解し、
水酸化ナトリウム２ｇ，水２０ｍｌを加え、３時間加熱
還流した。反応液に水３ ０ ０ ｍｌを加え、濃塩酸
にて弱酸性とし、析出した結晶を冫戸取した。水洗、乾
燥後３ｇ（８２．６％）の目的物を得た。このものをエ
タノールより再結晶すると微黄色結晶となる。4. removing the solvent; Brown crystals of Hg were obtained. Silica gel column chromatography (ethyl acetate:hexane 1;
3) to obtain 3.75 g (69.4%) of slightly yellow crystals. Dissolve this in 50ml of ethanol,
2 g of sodium hydroxide and 20 ml of water were added, and the mixture was heated under reflux for 3 hours. 300 ml of water was added to the reaction solution, made weakly acidic with concentrated hydrochloric acid, and the precipitated crystals were collected. After washing with water and drying, 3 g (82.6%) of the target product was obtained. When this product is recrystallized from ethanol, it becomes pale yellow crystals.
融点２１９〜２２０℃
元素分析値（％）： Ｃ２１｝｛２２Ｎ２ ０４Ｓとし
て
Ｃ ＨＮ
計算値 ６５、３８ ５．２５ ５．６３実測
値 ６５，２９ ５、１８ ６．５６合成例８
２〜（４−イソプロボキシフエニル）−１ ２ ３ ４
−テトラヒドロキノリン−８−カルボン酸
合成例６の化合物８１０■をＤＭＦ １５ｍｌに溶解し
、炭酸カリウムＩｇ，ヨウ化イソプロビル１．０７ｇを
加え、室温にて２２時間撹拌した。不溶物を枦去し、枦
液を濃縮後、残渣に酢酸エチル：ベンゼン・ｌ：Ｉ ２
００ｍｌを加え、よく水洗し、飽和食塩水で洗浄後、無
水硫酸ナトリウムで乾燥した。Melting point 219-220°C Elemental analysis value (%): C21}{22N2 C HN as 04S Calculated value 65, 38 5.25 5.63 Actual value 65,29 5, 18 6.56 Synthesis example 8 2-(4- isoproboxyphenyl)-1 2 3 4
-Tetrahydroquinoline-8-carboxylic acid Compound 810 of Synthesis Example 6 was dissolved in 15 ml of DMF, potassium carbonate Ig and 1.07 g of isoprobyl iodide were added, and the mixture was stirred at room temperature for 22 hours. After removing the insoluble matter and concentrating the solution, the residue was mixed with ethyl acetate:benzene.l:I 2
00 ml was added thereto, and the mixture was thoroughly washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate.
溶媒留去し、９３０■（８７．８％）の黄色浦状物を得
た。このものをエタノール１０ｍｌに溶解し、ＩＮ一水
酸化ナトリウム５ｍｌを加え、５時間加熱還流した。冷
却後、水５０ｍｌを加え、ＩＮ一塩酸にて弱酸性とし、
析出した結晶を枦取した。水洗、乾燥後７３０ｍｇ （
８９． １％）の目的物を得た。このものを酢酸エチル
ーヘキサンより再結晶すると黄色結晶となる。The solvent was distilled off, yielding 930 ml (87.8%) of a yellow gelatinous material. This product was dissolved in 10 ml of ethanol, 5 ml of IN sodium monohydroxide was added, and the mixture was heated under reflux for 5 hours. After cooling, add 50 ml of water and make weakly acidic with IN monohydrochloric acid.
The precipitated crystals were collected. After washing with water and drying, 730 mg (
89. 1%) of the target product was obtained. When this product is recrystallized from ethyl acetate-hexane, yellow crystals are obtained.
融点１６６〜１６７℃
元素分析値（％）：Ｃ．．ＨＪ，Ｎｏ．．とじてＣ
ＨＮMelting point: 166-167°C Elemental analysis value (%): C. ．． H.J., No. ．． Close C
HN
Claims (9)
水素原子、ハロゲン原子、炭素数１〜３の低級アルキル
基、炭素数１〜３の低級アルコキシ基、アミノ基、ニト
ロ基、ヒドロキシ基、スルホンアミド基、トリフルオロ
メチル基、シアノ基、カルボキシル基、カルバモイル基
、アセチル基、置換されていてもよいベンゾイルメチル
基、メチルチオ基、置換されていてもよいフェニルエチ
ニル基、置換されていてもよいエチニル基、炭素数１〜
３の低級アルカノイルアミノ基、置換されていてもよい
ベンゾイルアミノ基、炭素数１〜３の低級アルキルスル
ホニルアミノ基又は置換されていてもよいフェニルスル
ホニルアミノ基を、Ｒ＾４又はＲ＾５は同一又は相異な
って水素原子、炭素数１〜３の低級アルキル基、シアノ
基、カルボキシル基、ヒドロキシメチル基、置換されて
いてもよいフェニル基又はベンジル基を、Ｒ＾６は水素
原子、炭素数１〜３の低級アルキル基又はベンジル基を
、Ｘはメチレン基、酸素原子、イオウ原子、スルフィニ
ル基又はスルフォニル基を表す］ で示される環状アントラニル酸誘導体、それらの酸付加
塩又はアルカリ塩の少なくとも一種以上を有効成分とす
る代謝性骨疾患治療剤。(1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R^1, R^2, and R^3 are the same or different and represent a hydrogen atom, a halogen atom, or a carbon number of 1 -3 lower alkyl group, lower alkoxy group having 1 to 3 carbon atoms, amino group, nitro group, hydroxy group, sulfonamide group, trifluoromethyl group, cyano group, carboxyl group, carbamoyl group, acetyl group, substituted optional benzoylmethyl group, methylthio group, optionally substituted phenylethynyl group, optionally substituted ethynyl group, carbon number 1-
3 lower alkanoylamino group, optionally substituted benzoylamino group, lower alkylsulfonylamino group having 1 to 3 carbon atoms, or optionally substituted phenylsulfonylamino group, R^4 or R^5 are the same or a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a cyano group, a carboxyl group, a hydroxymethyl group, an optionally substituted phenyl group or a benzyl group, where R^6 is a hydrogen atom and a carbon number 1 ~3 lower alkyl group or benzyl group, X represents a methylene group, an oxygen atom, a sulfur atom, a sulfinyl group, or a sulfonyl group] At least one of the following cyclic anthranilic acid derivatives, acid addition salts or alkali salts thereof A therapeutic agent for metabolic bone diseases containing as an active ingredient.
ニル−１，２，３，４−テトラヒドロキノリン−８−カ
ルボン酸である請求項１記載の代謝性骨疾患治療剤。(2) The therapeutic agent for metabolic bone disease according to claim 1, wherein the compound as an active ingredient is 6-chloro-2-phenyl-1,2,3,4-tetrahydroquinoline-8-carboxylic acid.
，３，４−テトラヒドロキノリン−８−カルボン酸であ
る請求項１記載の代謝性骨疾患治療剤。(3) The compound as an active ingredient is 2-phenyl-1,2
, 3,4-tetrahydroquinoline-8-carboxylic acid, the therapeutic agent for metabolic bone disease according to claim 1.
３，４−テトラヒドロキノリン−８−カルボン酸である
請求項１記載の代謝性骨疾患治療剤。(4) The compound as an active ingredient is 6-nitro-1,2,
The therapeutic agent for metabolic bone diseases according to claim 1, which is 3,4-tetrahydroquinoline-8-carboxylic acid.
３，４−テトラヒドロキノリン−８−カルボン酸である
請求項１記載の代謝性骨疾患治療剤。(5) The compound as an active ingredient is 6-chloro-1,2,
The therapeutic agent for metabolic bone diseases according to claim 1, which is 3,4-tetrahydroquinoline-8-carboxylic acid.
，３，４−テトラヒドロキノリン−８−カルボン酸であ
る請求項１記載の代謝性骨疾患治療剤。(6) The compound as an active ingredient is 3-phenyl-1,2
, 3,4-tetrahydroquinoline-8-carboxylic acid, the therapeutic agent for metabolic bone disease according to claim 1.
フェニル）−１，２，３，４−テトラヒドロキノリン−
８−カルボン酸である請求項１記載の代謝性骨疾患治療
剤。(7) The compound as an active ingredient is 2-(4-hydroxyphenyl)-1,2,3,4-tetrahydroquinoline-
The therapeutic agent for metabolic bone diseases according to claim 1, which is 8-carboxylic acid.
−トルエンスルホニルアミノ−１，２，３，４−テトラ
ヒドロキノリン−８−カルボン酸である請求項１記載の
代謝性骨疾患治療剤。(8) The compound as an active ingredient is 2-phenyl-6-p
The therapeutic agent for metabolic bone disease according to claim 1, which is -toluenesulfonylamino-1,2,3,4-tetrahydroquinoline-8-carboxylic acid.
キシフェニル）−１，２，３，４−テトラヒドロキノリ
ン−８−カルボン酸である請求項１記載の代謝性骨疾患
治療剤。(9) The therapeutic agent for metabolic bone disease according to claim 1, wherein the compound as an active ingredient is 2-(4-isopropoxyphenyl)-1,2,3,4-tetrahydroquinoline-8-carboxylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15017290A JPH0395117A (en) | 1989-06-13 | 1990-06-08 | Metabolic bone disease therapeutic agent |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1-149988 | 1989-06-13 | ||
| JP14998889 | 1989-06-13 | ||
| JP15017290A JPH0395117A (en) | 1989-06-13 | 1990-06-08 | Metabolic bone disease therapeutic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0395117A true JPH0395117A (en) | 1991-04-19 |
Family
ID=26479714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15017290A Pending JPH0395117A (en) | 1989-06-13 | 1990-06-08 | Metabolic bone disease therapeutic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0395117A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5114890A (en) * | 1988-09-02 | 1992-05-19 | Teledyne Industries, Inc. | Zirconium-containing coating composition |
| JP2007069242A (en) * | 2005-09-07 | 2007-03-22 | Amada Co Ltd | Press brake |
| JP2008545805A (en) * | 2005-06-13 | 2008-12-18 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Tetrahydroquinoline used in the form of a regulator of the mitotic motor protein EG5 |
-
1990
- 1990-06-08 JP JP15017290A patent/JPH0395117A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5114890A (en) * | 1988-09-02 | 1992-05-19 | Teledyne Industries, Inc. | Zirconium-containing coating composition |
| JP2008545805A (en) * | 2005-06-13 | 2008-12-18 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Tetrahydroquinoline used in the form of a regulator of the mitotic motor protein EG5 |
| JP2007069242A (en) * | 2005-09-07 | 2007-03-22 | Amada Co Ltd | Press brake |
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