JPS63201123A - Remedy for osteoporosis - Google Patents
Remedy for osteoporosisInfo
- Publication number
- JPS63201123A JPS63201123A JP3198887A JP3198887A JPS63201123A JP S63201123 A JPS63201123 A JP S63201123A JP 3198887 A JP3198887 A JP 3198887A JP 3198887 A JP3198887 A JP 3198887A JP S63201123 A JPS63201123 A JP S63201123A
- Authority
- JP
- Japan
- Prior art keywords
- benzopyran
- phenyl
- derivative
- formula
- osteoporosis
- 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.)
- Granted
Links
- 208000001132 Osteoporosis Diseases 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 10
- 150000004777 chromones Chemical class 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims 5
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 208000006386 Bone Resorption Diseases 0.000 abstract description 14
- 230000024279 bone resorption Effects 0.000 abstract description 14
- 239000000203 mixture Substances 0.000 abstract description 11
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N flavone Chemical class O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 abstract description 8
- 230000011164 ossification Effects 0.000 abstract description 7
- 230000001737 promoting effect Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000002775 capsule Substances 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 4
- 150000008062 acetophenones Chemical class 0.000 abstract description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000843 powder Substances 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 abstract description 3
- 239000011230 binding agent Substances 0.000 abstract description 2
- NZZIMKJIVMHWJC-UHFFFAOYSA-N dibenzoylmethane Chemical class C=1C=CC=CC=1C(=O)CC(=O)C1=CC=CC=C1 NZZIMKJIVMHWJC-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007884 disintegrant Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract description 2
- 238000002347 injection Methods 0.000 abstract description 2
- 239000000314 lubricant Substances 0.000 abstract description 2
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 238000007911 parenteral administration Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 210000000988 bone and bone Anatomy 0.000 description 25
- 239000000243 solution Substances 0.000 description 21
- 239000011575 calcium Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 229910052791 calcium Inorganic materials 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000001963 growth medium Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZXTHWIZHGLNEPG-UHFFFAOYSA-N 2-phenyl-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC=C1 ZXTHWIZHGLNEPG-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical class C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 7
- 210000000689 upper leg Anatomy 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000287828 Gallus gallus Species 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 210000001161 mammalian embryo Anatomy 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 150000002212 flavone derivatives Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000012136 culture method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229930012930 isoflavone derivative Natural products 0.000 description 2
- 150000002515 isoflavone derivatives Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- ZTHLHHDJRXJGRX-UHFFFAOYSA-N neglectein Natural products C=1C(=O)C=2C(O)=C(O)C(OC)=CC=2OC=1C1=CC=CC=C1 ZTHLHHDJRXJGRX-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 1
- BEXQNGUXPFGRDC-UHFFFAOYSA-N 2,2-dimethoxy-1,3-diphenylpropane-1,3-dione Chemical compound C=1C=CC=CC=1C(=O)C(OC)(OC)C(=O)C1=CC=CC=C1 BEXQNGUXPFGRDC-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- CPBJMKMKNCRKQB-UHFFFAOYSA-N 3,3-bis(4-hydroxy-3-methylphenyl)-2-benzofuran-1-one Chemical compound C1=C(O)C(C)=CC(C2(C3=CC=CC=C3C(=O)O2)C=2C=C(C)C(O)=CC=2)=C1 CPBJMKMKNCRKQB-UHFFFAOYSA-N 0.000 description 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 206010016454 Femur fracture Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 206010039984 Senile osteoporosis Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 229940037448 calcitonin preparations Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 208000030212 nutrition disease Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007306 turnover Effects 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
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明の目的は、一般式（１）
（式中のＲＩＳＲ２およびＲ３は同じでも異なっていて
もよく、それぞれ水素原子または炭素数１〜３のアルキ
ル基である）で表される２−フェニル−４８−１−ベン
ゾピラン−４−オン誘導体またはそれらの薬理学的に許
容できる塩を含有する骨粗髭症治療剤を提供するもので
ある。Detailed Description of the Invention [Industrial Field of Application] The object of the present invention is to solve the problem of the general formula (1) (where RISR2 and R3 may be the same or different, and each has a hydrogen atom or a carbon number of 1 to 3 The present invention provides a therapeutic agent for osteoporosis containing a 2-phenyl-48-1-benzopyran-4-one derivative represented by (which is an alkyl group) or a pharmacologically acceptable salt thereof.
骨粗髭症とは骨の化学的組成に変化を来すことなく、骨
量の減少した病態をいい、骨中の蛋白、カルシウムおよ
びリンの減少がその生理的な特徴である。Osteoporosis is a pathological condition in which bone mass is decreased without any change in the chemical composition of bones, and its physiological characteristic is a decrease in protein, calcium, and phosphorus in bones.
骨粗髭症は加齢とともに増加し、通常を髄を侵し、腰背
痛および身長の短縮を起こす。特に進行した例では、長
管骨も侵されるので、ときに骨折を起こす場合もある。Osteoporosis increases with age and usually affects the spinal cord, causing back pain and shortened height. In particularly advanced cases, long bones are also affected, sometimes resulting in fractures.
老年者にみられる大腿骨骨折の原因のほとんどは老人性
骨粗髭症によるものであるといわれている。It is said that most of the causes of femur fractures seen in the elderly are due to senile osteoporosis.
この骨粗髭症の原因は内分泌および栄養障害等多種多様
であり、治療剤としてビタミンＤ製剤、カルシウム製剤
、カルシトニン製剤、リン製剤等が使用されているが、
その効果が確実でないために、より効果が確実な製剤の
開発が強く望まれている。The causes of osteoporosis are diverse, including endocrine and nutritional disorders, and vitamin D preparations, calcium preparations, calcitonin preparations, phosphorus preparations, etc. are used as therapeutic agents.
Since its effectiveness is uncertain, there is a strong desire to develop a formulation with more reliable efficacy.
近年、上記製剤とは化学構造を全く異にするある種の３
−フェニル−４）１−１−ベンゾピラン−４−オン誘導
体くイソフラボン誘導体）が骨吸収抑制作用を有し、骨
粗髭症の治療剤として有用であることが報告されている
（特公昭５４−１３３９１号、特開昭６０−４８９２４
号、特開昭６０−５４３７９号、特開昭６０−１３２９
１７号、特開昭６０−１３２９７６号）。In recent years, a certain type of drug with a completely different chemical structure from the above-mentioned preparations has been developed.
It has been reported that phenyl-4) 1-1-benzopyran-4-one derivatives (isoflavone derivatives) have a bone resorption inhibitory effect and are useful as therapeutic agents for osteoporosis. No. 13391, JP-A-60-48924
No., JP-A-60-54379, JP-A-60-1329
No. 17, JP-A-60-132976).
しかしながら、本発明の２−フェニル−４Ｈ−１−ベン
ゾピラン−４−オン誘導体（フラボン誘導体）またはそ
れらの薬理学的に許容できる塩が骨吸収抑制作用を示し
、骨粗髭症治療剤として有用であることは今まで全く報
告されていない。However, the 2-phenyl-4H-1-benzopyran-4-one derivatives (flavone derivatives) or their pharmacologically acceptable salts of the present invention exhibit bone resorption inhibitory effects and are not useful as therapeutic agents for osteoporosis. Some things have never been reported until now.
前記特許出願に開示されている３−フェニル−４８−１
−ベンゾピラン−４−オン誘導体（イソフラボン誘導体
）の骨吸収抑制作用は弱く、骨粗髭症の治療剤としては
決して満足できるものでない。それ故、本発明者らはベ
ンゾピラン−４−オン誘導体の骨吸収抑制作用について
鋭意検討したところ、ある種の２−フェニル−４Ｈ−１
−ベンゾピラン−４−オン誘導体（フラボン誘導体）ま
たはそれらの薬理学的に許容できる塩が強い骨吸収抑制
作用を有し、かつ骨形成促進作用をも示し、より優れた
骨粗髭症治療剤になり得ることを見出した。3-phenyl-48-1 disclosed in said patent application
-Benzopyran-4-one derivatives (isoflavone derivatives) have a weak bone resorption inhibitory effect and are by no means satisfactory as therapeutic agents for osteoporosis. Therefore, the present inventors conducted extensive studies on the bone resorption inhibitory effect of benzopyran-4-one derivatives, and found that certain 2-phenyl-4H-1
- Benzopyran-4-one derivatives (flavone derivatives) or their pharmacologically acceptable salts have a strong bone resorption inhibitory effect and also exhibit a bone formation promoting effect, making them an excellent osteoporosis treatment agent. I found out what is possible.
本発明はこれらの知見に基づくものである。The present invention is based on these findings.
本発明の前記一般式（Ｉ）で表される２−フェニル−４
日−１−ベンゾピラン−４−オン誘導体（フラボン誘導
体）またはそれらの薬理学的に許容できる塩は強い骨吸
収抑制作用と骨形成促進作用を示し、安全性の高い骨粗
髭症治療剤として有用である。2-phenyl-4 represented by the general formula (I) of the present invention
1-Benzopyran-4-one derivatives (flavone derivatives) or their pharmacologically acceptable salts exhibit strong bone resorption inhibitory and bone formation promoting effects and are useful as highly safe osteoporosis treatment agents. It is.
本発明の前記一般式（Ｉ）で表される２−フェニル−４
日−１−ベンゾピラン−４−オン誘導体は公知化合物で
あり、文献記載の方法またはその類似方法に従い製造す
ることができる。例えば、オルガニック シンセシス
コレクティブ ボリュウム ■、４７８〜４８１ページ
（Ｏｒｇ、Ｓｙｎ、 Ｃｏ１１． Ｖｏｌ、ＩＶ。2-phenyl-4 represented by the general formula (I) of the present invention
The di-1-benzopyran-4-one derivative is a known compound and can be produced according to methods described in literature or similar methods thereof. For example, organic synthesis
Collective Volume ■, pages 478-481 (Org, Syn, Co11. Vol, IV.
４７８〜４８１） ； ブロシーディングズ オン ザ
インディアン アカデミ−オン サイエンスズ（Ｐｒ
ｏｃ、 Ｉｎｄｉａｎ Ａｃａｄ、 Ｓｃｉ、）
３７Ａ 、 ６２９ページ、（１９５３年）； ジャ
ーナル オン ザ アメリカンケミカル ソサエティ、
（Ｊ、＾、Ｃ，Ｓ、） ７７巻、５３９０ページ（１９
５５年）； 日本化学雑誌１９巻、１２号１２７０ペー
ジ（１９６９年）等の方法またはその類似方法により容
易に製造することができる。478-481) ; Bros. on the Indian Academy of Sciences (Pr.
oc, Indian Acad, Sci,)
37A, page 629, (1953); Journal on the American Chemical Society,
(J, ^, C, S,) Volume 77, page 5390 (19
It can be easily produced by the method described in Nippon Kagaku Zasshi Vol. 19, No. 12, p. 1270 (1969) or similar methods.
すなわち、前記一般式（１）で表される２−フェニル−
４Ｈ−１−ベンゾピラン−４−オン誘導体は、一般式
（式中のＲ１、Ｒ２およびＲ３は前記と同じ意味をもつ
）で表されるアセトフェノン誘導体を塩化ベンゾイルと
反応させて、一般式
（式中のＲ４、Ｒ５およびＲ６はベンゾイル基または炭
素数１〜３のアルキル基である）で表されるベンゾイル
オキシアセトフェノン誘導体を得たのち、このものをペ
イカーベン力タラマン転位（ＢａｋｅｒＶｅｎｋａｔａ
ｒａｍａｎ ｒｅａｒｒａｎｇｅｍｅｎｔ） により
、式（式中のＲ４、Ｒ５およびＲ６は前記と同じ意味を
もつ）で表されるジベンゾイルメタン誘導体とし、次い
で酢酸中酢酸ナトリウムの存在下で脱水閉環させ、必要
ならば加水分解することにより製造することができる。That is, 2-phenyl- represented by the general formula (1)
4H-1-benzopyran-4-one derivatives are produced by reacting an acetophenone derivative represented by the general formula (in which R1, R2, and R3 have the same meanings as above) with benzoyl chloride. R4, R5 and R6 are a benzoyl group or an alkyl group having 1 to 3 carbon atoms.
raman rearrangement) to obtain a dibenzoylmethane derivative represented by the formula (in which R4, R5 and R6 have the same meanings as above), followed by dehydration and ring closure in the presence of sodium acetate in acetic acid, followed by hydration if necessary. It can be produced by decomposition.
本発明の前記一般式（Ｉ）で表される２−フェニル−４
Ｈ−１−ベンゾピラン−４−オン誘導体の５位のアルコ
キシ基は適当な酸性条件により選択的に脱アルキル化す
ることができ、ハイドロオキシ体とすることができる。2-phenyl-4 represented by the general formula (I) of the present invention
The alkoxy group at the 5-position of the H-1-benzopyran-4-one derivative can be selectively dealkylated under appropriate acidic conditions to form a hydroxy compound.
また、本発明の前記一般式（１）で表される２−フェニ
ル−４日−１−ベンゾピラン−４−オン誘導体でＲ１、
Ｒ２およびＲ３が炭素数１〜３のアルコキシ基である化
合物は、Ｒ’、Ｒ’およびＲ３のうち少なくとも１つが
水素原子である本発明の２−フェニル−４Ｈ−１−ベン
ゾピラン−４−オン誘導体をアルキルハライドと反応さ
せることにより製造することもできる。In addition, R1 in the 2-phenyl-4-day-1-benzopyran-4-one derivative represented by the general formula (1) of the present invention,
The compound in which R2 and R3 are alkoxy groups having 1 to 3 carbon atoms is the 2-phenyl-4H-1-benzopyran-4-one derivative of the present invention in which at least one of R', R' and R3 is a hydrogen atom. It can also be produced by reacting with an alkyl halide.
本製造方法において、原料として使用する前記一般式（
ＩＩ）で表されるアセトフェノン誘導体は公知化合物で
あり、文献記載の方法、例えばジャーナル オン ザ
ケミカル ソサエティー（Ｊ。In this production method, the general formula (
The acetophenone derivative represented by II) is a known compound, and the method described in the literature, for example, Journal on the
Chemical Society (J.
Ｃ，Ｓ、） １９４１年、６６２ページ〜、記載の方法
またはその類似方法に従い製造することができる。C,S,) 1941, p. 662~, or a method similar thereto.
本発明の前記一般式（１）で表される２−フェニル−４
Ｈ−１−ベンゾピラン−４−オン誘導体で、Ｒ１、Ｒ２
およびＲ３のうち少なくとも１つが水素原子である化合
物は、常法に従い薬理学的に許容できる塩とすることが
できる。例えば、本発明の一般式（Ｉ）で表される２−
フェニル−４日−１−ベンゾピラン−４−オン誘導体を
これと当量の水酸化ナトリウムを溶解したアルコール溶
液に加え、加温したのち、減圧下に濃縮することにより
ナトリウム塩とすることができる。2-phenyl-4 represented by the general formula (1) of the present invention
H-1-benzopyran-4-one derivative, R1, R2
A compound in which at least one of R3 and R3 is a hydrogen atom can be converted into a pharmacologically acceptable salt according to a conventional method. For example, 2- represented by the general formula (I) of the present invention
The phenyl-4-day-1-benzopyran-4-one derivative can be added to an alcoholic solution containing an equivalent amount of sodium hydroxide, heated, and then concentrated under reduced pressure to obtain the sodium salt.
本発明の前記一般式（１’）で表される２−フェニル−
４８−１−ベンゾピラン−４−オン誘導体は常法に従い
、医薬品製剤とすることができる。すなわち、通常用い
られる賦形剤、崩壊剤、結合剤、滑沢剤等の医薬品添加
物を混合し、常法に従い調剤し種々の製剤、例えば錠剤
、散剤、カプセル剤等とすることができる。2-phenyl- represented by the general formula (1') of the present invention
The 48-1-benzopyran-4-one derivative can be made into a pharmaceutical preparation according to a conventional method. That is, it is possible to mix commonly used pharmaceutical additives such as excipients, disintegrants, binders, lubricants, etc., and prepare according to conventional methods to form various preparations such as tablets, powders, capsules, etc.
本発明の前記一般式（１）で表される２−フェニル−４
Ｈ−１−ベンゾピラン−４−オン誘導体を骨粗髭症治療
剤として用いる場合、大人１日当り約ｌＯ〜１０００ｍ
ｇを適宜な剤型、例えば錠剤、散剤、カプセル剤などに
し、分層経口投与するか、または大人１日当り約１〜１
００＋ｎｇを注射剤等にして非経口投与する。2-phenyl-4 represented by the general formula (1) of the present invention
When H-1-benzopyran-4-one derivatives are used as a therapeutic agent for osteoporosis, approximately 10 to 1000 m/day for adults.
g in an appropriate dosage form, such as tablets, powders, capsules, etc., and administer orally in divided doses, or approximately 1 to 1 g per day for adults.
00+ng is administered parenterally in the form of an injection or the like.
本発明の前記一般式（Ｉ）で表される２−フェニル−４
Ｈ−１−ベンゾピラン−４−オン誘導体またはそれらの
薬理学的に許容できる塩は鶏胚大腿骨を用いた試験管内
実験において、強い骨吸収抑制作用と骨形成促進作用を
示し、かつカルシウム欠乏食餌を与えた時に生じるラッ
トの骨中のカルシウムおよびリンの含有量の減少を著し
く抑制させる作用を有し、安全性の高い骨粗鬆症治療剤
として有用である。2-phenyl-4 represented by the general formula (I) of the present invention
H-1-benzopyran-4-one derivatives or their pharmacologically acceptable salts have shown strong bone resorption-inhibiting and osteogenic-promoting effects in in vitro experiments using chicken embryo femurs, and have been found to be effective against calcium-deficient diets. It has the effect of significantly suppressing the decrease in calcium and phosphorus content in the bones of rats that occurs when given to rats, and is useful as a highly safe osteoporosis treatment agent.
本発明をさらに詳述するために以下に実施例をあげる。 Examples are given below to further explain the present invention.
なお、実施例中の化合物の融点は未補正である。Note that the melting points of the compounds in the Examples are uncorrected.
実施例 １
セトフエノン
３．６−ジハイドロオキシー２．４−ジメトキシアセト
フェノン３４ ｇを乾燥ピリジン７０ｍ１に溶解し、こ
の溶液に塩化ベンゾイル４’Ｏｍｌを加え、水浴上で３
０分間加温する。反応液を冷却後、希塩酸で酸性とし析
出結晶をろ取する。析出結晶をクロロホルム１１に溶解
し、無水硫酸マグネシウムで乾燥する。Example 1 Cetophenone 34 g of 3,6-dihydroxy-2,4-dimethoxyacetophenone was dissolved in 70 ml of dry pyridine, 4'Oml of benzoyl chloride was added to this solution, and 34 g of cetophenone was dissolved on a water bath.
Warm for 0 minutes. After cooling the reaction solution, it is made acidic with dilute hydrochloric acid and the precipitated crystals are collected by filtration. The precipitated crystals are dissolved in 11 chloroform and dried over anhydrous magnesium sulfate.
減圧下でクロロホルム溶液を約３００ｍｌまで濃縮し、
この溶液にメタノール５００ｄを加え一夜放置する。Concentrate the chloroform solution to about 300 ml under reduced pressure,
Add 500 d of methanol to this solution and leave it overnight.
析出結晶をろ取し、３，６−ジベンシイルオキシー２゜
４−ジメトキシアセトフェノン５１．６ｇを得る。The precipitated crystals were collected by filtration to obtain 51.6 g of 3,6-dibensiloxy-2.4-dimethoxyacetophenone.
融 点： １５３〜１５５℃
３．６−ジベンゾイルオキシ−２，４−ジメトキシアセ
トフエノン１６２．２ｇを乾燥Ｎ、Ｎ−ジメチルホルム
アミドに溶解し、この溶液に５５％水素化ナトリウム（
油性）２０．３ｇを攪拌下に少量ずつ加える。その後約
３０分間攪拌したのち、水３１中に反応液を注ぎ、希塩
酸で酸性とする。析出する結晶をろ取し水洗後、クロロ
ホルム１．５１に溶解し、無水硫酸マグネシウムで乾燥
後、減圧下に濃縮する。残渣にｎ−ヘキサンを加え、析
出した褐色ゲル状物質をろ去したのち、析出結晶をろ取
し、３−ベンゾイルオキシ−６−ハイドロオキシ−２，
４−ジメトキシジベンゾイルメタン１２０．８ ｇを得
る。Melting point: 153-155°C 162.2 g of 3.6-dibenzoyloxy-2,4-dimethoxyacetophenone was dissolved in dry N,N-dimethylformamide, and 55% sodium hydride (
Add 20.3 g of oil-based oil little by little while stirring. After stirring for about 30 minutes, the reaction solution was poured into water 31 and made acidic with dilute hydrochloric acid. The precipitated crystals are collected by filtration, washed with water, dissolved in 1.5 g of chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After adding n-hexane to the residue and filtering off the precipitated brown gel-like substance, the precipitated crystals were collected by filtration, and 3-benzoyloxy-6-hydroxy-2,
120.8 g of 4-dimethoxydibenzoylmethane are obtained.
融 点 ： １３９〜１４１℃
３−ベンゾイルオキシ−６−ハイドロオキシ−２，４−
ジメトキシジベンゾイルメタン３０．０ｇ、酢酸ナトリ
ウム（油性）３０ｇおよび酢酸１７０ ｒｎｌの混合物
を３時間加熱還流する。反応液を氷水中に注ぎ、析出結
晶をろ取する。この結晶をメタノールで再結晶して６−
ペンゾイルオキシー５．７−シメトキシー２−フェニル
−４Ｈ−１−ベンゾピラン−４−オン２０．５ｇを得る
。Melting point: 139-141°C 3-benzoyloxy-6-hydroxy-2,4-
A mixture of 30.0 g of dimethoxydibenzoylmethane, 30 g of sodium acetate (oil) and 170 rnl of acetic acid is heated under reflux for 3 hours. Pour the reaction solution into ice water and filter the precipitated crystals. This crystal was recrystallized from methanol to give 6-
20.5 g of penzoyloxy-5.7-simethoxy-2-phenyl-4H-1-benzopyran-4-one are obtained.
融 点 ： ２１６〜２１８℃
６−ベンゾイルオキシ−５パージメトキシ−２−フェニ
ル−４日−１−ベンゾピラン−４−オン５６．６ｇをメ
タノール８１にけんだくし、このけんだく液に水酸化カ
リウム５７ ｇを含む水溶液１２０ｍｅを加え、水浴上
で加温し溶解する。反応液を減圧下で濃縮し、残渣を１
１の水に溶かし、氷冷し析出結晶をろ取する。この結晶
をメタノールで再結晶して６−ハイドロオキシ−５，７
−シメトキシー２−フェニル−４日−１−ベンゾピラン
−４−オン２８Ｊｇを得る。Melting point: 216-218°C 56.6 g of 6-benzoyloxy-5-perdimethoxy-2-phenyl-4-1-benzopyran-4-one was suspended in 81 g of methanol, and 57 g of potassium hydroxide was added to the suspension. Add 120me of an aqueous solution containing g and dissolve by heating on a water bath. The reaction solution was concentrated under reduced pressure, and the residue was
Dissolve in water from Step 1, cool on ice, and filter the precipitated crystals. This crystal was recrystallized from methanol to give 6-hydroxy-5,7
-Simethoxy2-phenyl-4day-1-benzopyran-4-one 28 Jg are obtained.
融 点＝ ２１７〜２１９℃
元素分析値： （Ｃ＋ＪｚＯｓとして）６％ Ｈ
％
計算値 ６ｇ、４５ ４．７３
実測値 ６８．４２ ４．６２
実施例 ２
６−ハイドロオキシ−５，７−シメトキシー２−フェニ
ル−４日−１−ベンゾピラン−４−オン２ｇ１無氷炭酸
カリウム７ｇ、ヨウ化メチル７ｒｄ！、および乾燥アセ
トン７０ｒｎｌの混合物を２４時間加熱還流する。反応
液をろ過し、不溶物をろ去し、ろ液を濃縮する。残渣を
エタノールから再結晶し、５．６．７〜トリメトキシ−
２−フェニル−４日−１−ベンゾピラン−４−オン１．
７ｇを得る。Melting point = 217-219℃ Elemental analysis value: (as C + JzOs) 6% H
% Calculated value 6g, 45 4.73 Actual value 68.42 4.62 Example 2 6-Hydroxy-5,7-simethoxy2-phenyl-4day-1-benzopyran-4-one 2g1 Ice-free potassium carbonate 7g , methyl iodide 7rd! , and 70 rnl of dry acetone is heated to reflux for 24 hours. The reaction solution is filtered, insoluble materials are removed by filtration, and the filtrate is concentrated. The residue was recrystallized from ethanol and 5.6.7~trimethoxy-
2-phenyl-4-1-benzopyran-4-one 1.
Obtain 7g.
融 点： １６７〜１７０℃
元素分析値’ （Ｃ＋ｓＨ＋ｇｌｌｓとして）０％
Ｈ％
計算値 ６９．２２ ５．１６
実測値 ６９．０３ ５．１６
実施例 ３
５、６．７−ドリメトキシー２−フェニル−４Ｈ−１−
ベンゾピラン−４−オン１ｇを酢酸および塩酸の混合物
（１：１）５０ｍｇに加え２時間加熱還流する。反応液
を水５００ ｍ／中に注ぎ、減圧下に約１００〜１５０
ｒｎ１になるまで濃縮する。析出結晶をろ取し、これを
エタノールで再結晶して５−ハイドロオキシ−６，７−
シメトキシー２−フェニル−４Ｈ−１〜ベンゾピラン−
４−オン０．５ｇを得る。Melting point: 167-170℃ Elemental analysis value (as C+sH+glls) 0%
H% Calculated value 69.22 5.16 Actual value 69.03 5.16 Example 3 5,6.7-Dorimethoxy-2-phenyl-4H-1-
1 g of benzopyran-4-one was added to 50 mg of a mixture of acetic acid and hydrochloric acid (1:1), and the mixture was heated under reflux for 2 hours. The reaction solution was poured into 500 m/m of water, and the
Concentrate until rn1. The precipitated crystals were collected by filtration and recrystallized with ethanol to give 5-hydroxy-6,7-
Cymethoxy 2-phenyl-4H-1-benzopyran-
0.5 g of 4-one is obtained.
融 点 ： １５８〜１６０℃
元素分析値’ （Ｃ＋Ｊ＋４０ｓとして）０％
Ｈ％
計算値 ６８．４５ ４．７３
実測値 ６８Ｊ６ ４．７２
実施例 ４
６−ハイドロオキシ−５，７−シメトキシー２−フェニ
ル−４Ｈ−１−ベンゾピラン−４−オン１ｇを酢酸およ
び塩酸の混合物（１：１）５０ｍｇに加え、２時間加熱
還流する。反応液を冷却後水５００ｄ中に注ぎ、次いで
減圧下に約１００〜１５０ｍ１になるまで濃縮する。Melting point: 158-160℃ Elemental analysis value' (as C+J+40s) 0%
H% Calculated value 68.45 4.73 Actual value 68J6 4.72 Example 4 1 g of 6-hydroxy-5,7-simethoxy-2-phenyl-4H-1-benzopyran-4-one was added to a mixture of acetic acid and hydrochloric acid ( 1:1) and heated under reflux for 2 hours. After cooling, the reaction solution is poured into 500 ml of water, and then concentrated under reduced pressure to a volume of about 100 to 150 ml.
析出結晶をろ取し、水洗したのち、エタノールで３回再
結晶し、５．６−ジハイドロオキシー７−メトキシー２
−フェニル−４Ｈ−１−ベンゾピラン−４−オン５００
ｍｇを得る。The precipitated crystals were collected by filtration, washed with water, and then recrystallized three times with ethanol to obtain 5,6-dihydroxy-7-methoxy 2
-Phenyl-4H-1-benzopyran-4-one 500
Get mg.
融 点 ： ２１９〜２２２℃
元素分析値’ （Ｃ＋ｓＨ＋□０．として）０％
Ｈ％
計算値 ６７．６０ ４．２６
実測値 ６７．６３ ４．２５
実施例 ５
骨吸収抑制作用
骨吸収抑制作用を「組織培養応用研究法」ページ１１１
〜１１４（山根績、遠藤浩良鳩集、ソフトサイエンス社
出版、 １９８５年）記載の方法に従い測定した。Melting point: 219-222℃ Elemental analysis value' (as C+sH+□0.) 0%
H% Calculated value 67.60 4.26 Actual value 67.63 4.25 Example 5 Bone resorption inhibitory effect Bone resorption inhibitory effect was evaluated in "Tissue Culture Applied Research Methods" page 111
-114 (Yamane Satoshi, Endo Hiroyoshi Hatoshu, Soft Science Publishing, 1985).
瞬卵１０−１１日の鶏胚大腿骨を摘出し、骨に付着する
柔組織をよく取り除いた後、本発明の２−フェニル−４
Ｈ−１−ベンゾピラン−４−オン誘導体を添加したフェ
ノールレッドを含有しないＢＧＪｂ−ＨＷ２培養液（以
下培養液という）ｌ−を用いて３７℃で１日間回転培養
法により前培養を行う。なお、本発明の化合物は一旦、
ジメチルスルホキサイドに溶解して、０．１モル濃度の
溶液を製し、これを培養液で１０００倍希釈し、１０−
４モル濃度とする。また、対照群は同容量のジメチルス
ルホキサイドのみを加えて培養を行う。After extracting the 10-11 day old chicken embryo femur and thoroughly removing the soft tissue attached to the bone, the 2-phenyl-4 of the present invention was extracted.
Preculture is carried out using a phenol red-free BGJb-HW2 culture medium (hereinafter referred to as culture medium) l- to which an H-1-benzopyran-4-one derivative has been added by a rotation culture method at 37° C. for one day. Note that the compound of the present invention is
Dissolve in dimethyl sulfoxide to prepare a 0.1 molar solution, dilute this 1000 times with culture medium, and make a 10-
The concentration is 4 molar. In addition, a control group is cultured by adding only the same volume of dimethyl sulfoxide.
翌日、新鮮な培養液に４ｓＣａＣＩ２をｔ μｃｉ ／
ｒｄの濃度に溶解し、前培養した鶏胚大腿骨をそのｔ
ａｉｌ！に浸漬し、３７℃にて２時間振盪培養する。こ
れにより培養骨中の骨塩は４ Ｓ （ａで標識される。The next day, add tμci/4sCaCI2 to fresh culture medium.
The chicken embryo femur, which had been dissolved and precultured at a concentration of rd, was
ail! and culture with shaking at 37°C for 2 hours. As a result, bone mineral in cultured bone is labeled with 4S (a).
培養終了後ただちにあらかじめ３７℃に加温しておいた
リン酸ａ衡生理食塩水で培養骨を洗浄して骨に付着して
いる４％Ｃａを取り除く。この４ Ｓ （ａの標識培養
骨を再び培養液で回転培養法（１０回回転時）により培
養する。１２．２４．４８．７２時間ごとに培養液から
正確に一定量の培養液を分取し、同時に残りの培養液を
揄で、新しい培養液を加える。分取した培養液中の４％
（ａ放射活性を液体シンチレーションカラターで測定し
、全培養液中の４ Ｓ Ｃａの放射活性を計算する。培
養終了後、骨組織を１規定塩酸中に１日放置し、全カル
シウムを溶出させ、その放射活性を測定し、培養骨中の
最終残存放射活性とする。Immediately after completion of the culture, the cultured bones are washed with a phosphate-balanced physiological saline that has been preheated to 37°C to remove 4% Ca adhering to the bones. This 4S (a) labeled cultured bone is again cultured in the culture medium using the rotational culture method (when rotated 10 times).12.24.48.7 Accurately collect a certain amount of culture medium from the culture medium every 2 hours. At the same time, scrape the remaining culture solution and add new culture solution.4% of the aliquoted culture solution.
(a) Radioactivity is measured using a liquid scintillation chromator, and the radioactivity of 4 S Ca in the total culture solution is calculated. After the culture is complete, the bone tissue is left in 1N hydrochloric acid for 1 day to elute the total calcium. , measure its radioactivity and use it as the final residual radioactivity in the cultured bone.
得られた測定値から、最初に骨組織に取り込まれた全放
射活性に対する培養骨中に残存している放射活性の割合
を算出し、２４時間以降の培養骨中の放射活性残存減衰
曲線で破骨細胞による骨塩溶出を直線回帰し、得られた
直線の勾配より、培養骨へ沈着した骨塩中のカルシウム
のターンオーバー率を生物学的半減期Ｔ’Ａとして求め
る。From the obtained measurement values, the ratio of the radioactivity remaining in the cultured bone to the total radioactivity initially incorporated into the bone tissue was calculated, and the decay curve of the residual radioactivity in the cultured bone after 24 hours was calculated. Bone mineral elution by bone cells is linearly regressed, and from the slope of the obtained straight line, the turnover rate of calcium in bone mineral deposited on cultured bone is determined as biological half-life T'A.
本発明の化合物群および対照群は各々１群５例で実施し
た。The compound group of the present invention and the control group were each conducted with 5 patients per group.
対照群のＴ’Ａの値と比較して、本発明の化合物群のＴ
’Ａの値が大きい値を示した場合、本発明の化合物は骨
吸収抑制作用を有することを示す。本発明の化合物の骨
吸収抑制作用の効力をＴ’Ａの値を用い、以下の式によ
り求める。Compared with the T'A value of the control group, the T'A value of the compound group of the present invention
'A large value of A indicates that the compound of the present invention has a bone resorption inhibitory effect. The efficacy of the bone resorption inhibitory effect of the compound of the present invention is determined by the following formula using the value of T'A.
結果を以下に示す。The results are shown below.
化 合 物 骨吸収抑制作用の効力実施例 ６
骨形成促進作用
骨形成促進作用を「組織培養応用研究法」ページ１０３
〜１１１ （山根績、遠藤浩良絹集、ソフトサイエン
ス社出版、 １９８５年）記載の方法に従い測定した。Compound Efficacy Example of Bone Resorption Inhibition Effect 6 Bone Formation Promoting Effect Bone formation promoting effect is shown in "Tissue Culture Applied Research Methods" page 103
~111 (Yamane Satoshi, Endo Hiroyoshi Kinshu, Soft Science Publishing, 1985).
岬卵９日の鶏胚大腿骨を摘出し、骨に付着する柔組織を
よく取り除き、１個体の左右の大腿骨のうち一方を本発
明の２−フェニル−４Ｈ−１−ベンゾピラン−４−オン
誘導体群、他方を対照群として用い、培養用平角試験管
の内面に一本ずつ付着させ、これにＢＧＪｂ−）ＩＷ２
培溶液（以下培養液という）２ｒｎｌを加えシリコン栓
で密栓し、３７℃で回転培養（１０回回転時間）する。9-day-old chicken embryo femurs were removed, the soft tissues attached to the bones were thoroughly removed, and one of the left and right femurs of each individual was treated with 2-phenyl-4H-1-benzopyran-4-one of the present invention. The derivative group and the other group were used as a control group, and each one was attached to the inner surface of a rectangular culture test tube, and BGJb-)IW2
Add 2 rnl of a culture solution (hereinafter referred to as culture solution), seal with a silicone stopper, and culture with rotation at 37°C (10 rotations).
本発明の化合物は一旦、ジメチルスルホキサイドに溶解
して０．１モル濃度の溶液を製し、これを、培養液でｌ
ロー４モル濃度になるよう１０００倍希釈する。また、
対照群には同容量のジメチルスルホキサイドのみを加え
て培養を行う。The compound of the present invention is first dissolved in dimethyl sulfoxide to prepare a solution with a concentration of 0.1 molar, and this is added to the culture solution in liters.
Dilute 1000 times to a low 4 molar concentration. Also,
A control group is cultured with the same volume of dimethyl sulfoxide alone added.
１日毎に骨の長さを測定しつつ、新鮮な培養液で交換し
ながら前培養を６日間継続する。Preculture is continued for 6 days while measuring bone length every day and replacing with fresh culture medium.
培養終了時に培養骨をリン酸緩衝生理食塩水で洗い、１
規定塩酸中に１日放置して、骨組織からカルシウムを溶
出させ、溶出したＣａ量をオルトクレゾールフタレイン
によりキレート法で定量する。At the end of the culture, wash the cultured bone with phosphate buffered saline,
The bone tissue is left in normal hydrochloric acid for one day to elute calcium from the bone tissue, and the amount of eluted Ca is determined by the chelation method using orthocresol phthalein.
本実験は各群６例で実施した。This experiment was conducted with 6 patients in each group.
本発明の化合物の骨形成促進作用の効力を以下の式によ
り求めた。The efficacy of the osteogenesis promoting effect of the compound of the present invention was determined using the following formula.
河照掛りし８重 結果を以下に示す。Kawaserukakeshi 8 layers The results are shown below.
化 合 物 骨形成促進作用の効力実施例 ７
３週齢のウィスター系雄性ラッ）２０匹を１群１０匹ず
つ２群に分け、１群に本発明の５．６．７− トＩＪメ
トキシー２−フェニル−４Ｈ−１−ベンゾピラン−４−
オン３００ ｍｇ ／ ｋｇをＣＭＣ！ｌ濁液で１日１
回、毎日強制的に経口投与し、他の１群には同容量のＣ
ＭＣ’のみを投与して、それぞれＣａ欠乏食を与えて２
週間飼育し、大腿骨の中のカルシウムおよびリン量を測
定した。Compound Efficacy Example 7 of Osteogenesis Promoting Effect 20 3-week-old Wistar male rats were divided into 2 groups of 10 rats each, and each group was treated with 5.6.7-IJ Methoxy 2 of the present invention. -Phenyl-4H-1-benzopyran-4-
On 300 mg/kg on CMC! l suspension per day
The other group received the same amount of C.
Administering only MC' and feeding Ca-deficient diet, respectively.
The animals were kept for a week, and the amounts of calcium and phosphorus in the femur were measured.
結果を以下に示す。The results are shown below.
実施例 ８
急性毒性
５．６．７−ドリメトキシー２−フェニル−４Ｈ−１−
ベンゾピラン−４−オンをＣＭＣにけんだくし、７週齢
ＩＣＲ系マウス雌雄各１０匹を用い、１０００．２００
０．３０００ｍｇ ／ ｋｇを経口投与し、７日間観察
した。いずれの群においても死亡例はなく、中毒症状も
認められなかった。Example 8 Acute Toxicity 5.6.7-Dorimethoxy2-phenyl-4H-1-
Benzopyran-4-one was suspended in CMC, and using 10 male and 10 male and 7-week-old ICR mice, 1000.200
0.3000 mg/kg was orally administered and observed for 7 days. There were no deaths and no symptoms of toxicity were observed in either group.
実施例 ９
製剤の製造
（ａ） 錠 剤
５．６．７−）ジメトキシ−２−フェニル−４Ｈ−１−
ベンゾピラン−４−オン１００ ｇ、乳糖９５ ｇおよ
びトウモロコシデンプン４０ ｇを混合し、次いで５％
ハイドロオキシプロピルセルロース水溶液を加えて練合
したのち、乾燥し、乾燥物にカルボキシメチルセルロー
スカルシウム８ｇおよびステアリン酸カルシウム７ｇを
加え混合したのち、１０００錠に成形する。Example 9 Manufacture of formulation (a) Tablet 5.6.7-) Dimethoxy-2-phenyl-4H-1-
Mix 100 g of benzopyran-4-one, 95 g of lactose and 40 g of corn starch, then 5%
After adding an aqueous hydroxypropylcellulose solution and kneading, the mixture is dried, and 8 g of carboxymethyl cellulose calcium and 7 g of calcium stearate are added to the dried product and mixed, and then molded into 1000 tablets.
（ｂ） カプセル剤
５．６．７−）ジメトキシ−２−フェニル−４Ｈ−１−
ベンゾピラン−４−オン１００ ｇ、乳糖５９ ｇおよ
びトウモロコシデンプン３５ ｇを混合し、さらに混合
物にタルク６ｇを加えて混合したのち、硬カプセル１０
００カプセルに充填する。(b) Capsules 5.6.7-)dimethoxy-2-phenyl-4H-1-
100 g of benzopyran-4-one, 59 g of lactose and 35 g of corn starch were mixed, and 6 g of talc was added to the mixture and mixed, followed by 10 hard capsules.
Fill into 00 capsules.
本発明の一般式（１）で表される２−フェニル−４日−
１−ベンゾピラン−４−オン誘導体およびそれらの薬理
学的に許容できる塩は鶏胚大腿骨を用いた試験管内実験
において、強い骨吸収抑制作用と骨形成促進作用を示し
、また、カルシウム欠乏食餌を与えた時に生じるラット
の骨中のカルシウムおよびリン含有量の減少を著しく抑
制する。2-phenyl-4-day- represented by general formula (1) of the present invention
1-benzopyran-4-one derivatives and their pharmacologically acceptable salts have shown strong bone resorption-inhibiting and osteogenic-promoting effects in in vitro experiments using chicken embryo femurs, and have also been found to be effective against calcium-deficient diets. It significantly suppresses the decrease in calcium and phosphorus content in the bones of rats that occurs when given.
従って、本発明の一般式（１）で表される２−フェニル
−４Ｈ−１−ベンゾピラン−４−オン誘導体は骨粗髭症
治療剤として有用である。Therefore, the 2-phenyl-4H-1-benzopyran-4-one derivative represented by the general formula (1) of the present invention is useful as a therapeutic agent for osteoporosis.
Claims (5)
ていてもよく、それぞれ水素原子または炭素原子数１〜
３のアルキル基である）で表される２−フェニル−４Ｈ
−１−ベンゾピラン−４−オン誘導体またはそれらの薬
理学的に許容できる塩を有効成分として含有する骨粗鬆
症治療剤。(1) General formulas ▲ Numerical formulas, chemical formulas, tables, etc.
2-phenyl-4H, which is an alkyl group of 3)
- A therapeutic agent for osteoporosis containing a 1-benzopyran-4-one derivative or a pharmacologically acceptable salt thereof as an active ingredient.
−オン誘導体またはその薬理学的に許容できる塩を有効
成分として含有する特許請求の範囲第１項記載の骨粗鬆
症治療剤。(2) 2-phenyl-4H-1-benzopyran-4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
The therapeutic agent for osteoporosis according to claim 1, which contains a -one derivative or a pharmacologically acceptable salt thereof as an active ingredient.
−オン誘導体またはその薬理学的に許容できる塩を有効
成分として含有する特許請求の範囲第１項記載の骨粗鬆
症治療剤。(3) 2-phenyl-4H-1-benzopyran-4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
The therapeutic agent for osteoporosis according to claim 1, which contains a -one derivative or a pharmacologically acceptable salt thereof as an active ingredient.
−オン誘導体を有効成分として含有する特許請求の範囲
第１項記載の骨粗鬆症治療剤。(4) 2-phenyl-4H-1-benzopyran-4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
The therapeutic agent for osteoporosis according to claim 1, which contains an -one derivative as an active ingredient.
−オン誘導体を有効成分として含有する特許請求の範囲
第１項記載の骨粗鬆症治療剤。(5) 2-phenyl-4H-1-benzopyran-4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
The therapeutic agent for osteoporosis according to claim 1, which contains an -one derivative as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3198887A JPH0729920B2 (en) | 1987-02-14 | 1987-02-14 | Osteoporosis treatment |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3198887A JPH0729920B2 (en) | 1987-02-14 | 1987-02-14 | Osteoporosis treatment |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63201123A true JPS63201123A (en) | 1988-08-19 |
| JPH0729920B2 JPH0729920B2 (en) | 1995-04-05 |
Family
ID=12346301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3198887A Expired - Lifetime JPH0729920B2 (en) | 1987-02-14 | 1987-02-14 | Osteoporosis treatment |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0729920B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003092666A1 (en) * | 2002-05-01 | 2003-11-13 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Calcium-containing tissue strengthening agents and use thereof |
| EP1556031A2 (en) * | 2002-10-22 | 2005-07-27 | Jenken Bioscience, Inc. | Chromones and chromone derivatives and uses thereof |
| CN104262311A (en) * | 2014-09-12 | 2015-01-07 | 福州大学 | Method for preparing baicalein-7-methyl ether |
-
1987
- 1987-02-14 JP JP3198887A patent/JPH0729920B2/en not_active Expired - Lifetime
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003092666A1 (en) * | 2002-05-01 | 2003-11-13 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Calcium-containing tissue strengthening agents and use thereof |
| US8778882B2 (en) | 2002-05-01 | 2014-07-15 | Hayashibara Co., Ltd. | Agent for strengthening calcium containing tissue and use thereof |
| EP1556031A2 (en) * | 2002-10-22 | 2005-07-27 | Jenken Bioscience, Inc. | Chromones and chromone derivatives and uses thereof |
| EP1556031A4 (en) * | 2002-10-22 | 2009-03-25 | Jenken Biosciences Inc | Chromones and chromone derivatives and uses thereof |
| CN104262311A (en) * | 2014-09-12 | 2015-01-07 | 福州大学 | Method for preparing baicalein-7-methyl ether |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0729920B2 (en) | 1995-04-05 |
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