JPH0769883A - Aromatase inhibitor - Google Patents
Aromatase inhibitorInfo
- Publication number
- JPH0769883A JPH0769883A JP5237140A JP23714093A JPH0769883A JP H0769883 A JPH0769883 A JP H0769883A JP 5237140 A JP5237140 A JP 5237140A JP 23714093 A JP23714093 A JP 23714093A JP H0769883 A JPH0769883 A JP H0769883A
- Authority
- JP
- Japan
- Prior art keywords
- xanthocillin
- aromatase
- group
- cancer
- dependent diseases
- 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
- 239000003886 aromatase inhibitor Substances 0.000 title claims abstract description 17
- 229940122815 Aromatase inhibitor Drugs 0.000 title claims abstract description 14
- 102000014654 Aromatase Human genes 0.000 claims abstract description 21
- 108010078554 Aromatase Proteins 0.000 claims abstract description 21
- YBMVKDUTYAGKEW-WHYMJUELSA-N 4-[(1z,3z)-4-(4-hydroxyphenyl)-2,3-diisocyanobuta-1,3-dienyl]phenol Chemical compound C1=CC(O)=CC=C1\C=C(/[N+]#[C-])\C(\[N+]#[C-])=C\C1=CC=C(O)C=C1 YBMVKDUTYAGKEW-WHYMJUELSA-N 0.000 claims abstract description 20
- OKFZCZSKKKVBDG-UHFFFAOYSA-N Xanthocillin X Natural products C1=CC(O)=CC=C1C=C(C#N)C(C#N)=CC1=CC=C(O)C=C1 OKFZCZSKKKVBDG-UHFFFAOYSA-N 0.000 claims abstract description 19
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 230000001419 dependent effect Effects 0.000 claims abstract description 13
- 239000005556 hormone Substances 0.000 claims abstract description 11
- 229940088597 hormone Drugs 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 230000000694 effects Effects 0.000 abstract description 9
- -1 sulfuric acid ester Chemical class 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 206010006187 Breast cancer Diseases 0.000 abstract description 3
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 3
- 206010033128 Ovarian cancer Diseases 0.000 abstract description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 abstract description 3
- 206010060862 Prostate cancer Diseases 0.000 abstract description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 abstract description 3
- 206010046798 Uterine leiomyoma Diseases 0.000 abstract description 3
- 206010046766 uterine cancer Diseases 0.000 abstract description 3
- 201000009273 Endometriosis Diseases 0.000 abstract 1
- 206010051482 Prostatomegaly Diseases 0.000 abstract 1
- 238000000034 method Methods 0.000 description 8
- NIFGBMKUAMIQJA-BKHHGCLFSA-N 4-[(1z,3z)-2,3-diisocyano-4-(4-methoxyphenyl)buta-1,3-dienyl]phenol Chemical compound C1=CC(OC)=CC=C1\C=C(/[N+]#[C-])\C(\[N+]#[C-])=C\C1=CC=C(O)C=C1 NIFGBMKUAMIQJA-BKHHGCLFSA-N 0.000 description 6
- DSUFFPKJNFNJNM-UHFFFAOYSA-N Xanthocillin-X-dimethyl-ether Natural products COc1ccc(C=C(/N=C)C(=Cc2ccc(OC)cc2)N=C)cc1 DSUFFPKJNFNJNM-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000003637 steroidlike Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 229940046844 aromatase inhibitors Drugs 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229940126585 therapeutic drug Drugs 0.000 description 3
- VJKZMXOJMQCHRI-AXPXABNXSA-N 1-[(1z,3z)-2,3-diisocyano-4-(4-methoxyphenyl)buta-1,3-dienyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1\C=C(/[N+]#[C-])\C(\[N+]#[C-])=C\C1=CC=C(OC)C=C1 VJKZMXOJMQCHRI-AXPXABNXSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- UKCVAQGKEOJTSR-UHFFFAOYSA-N Fadrozole hydrochloride Chemical compound Cl.C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 UKCVAQGKEOJTSR-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 201000002595 endometriosis of ovary Diseases 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 208000030747 ovarian endometriosis Diseases 0.000 description 2
- 210000002826 placenta Anatomy 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- AEMFNILZOJDQLW-WFZCBACDSA-N (10r,13s)-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1CC[C@]2(C)C3CC[C@](C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-WFZCBACDSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000228257 Aspergillus sp. Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241001374813 Dichotomomyces Species 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 229930187731 Xanthocillin Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical class O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 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
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003028 enzyme activity measurement method Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 239000002324 mouth wash Substances 0.000 description 1
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- 229930014626 natural product Natural products 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明はキサントシリンＸ及びそ
の類縁化合物がアロマターゼ阻害活性を有することを見
いだし、この作用を利用したアロマターゼ阻害剤に関す
る。本発明のアロマターゼ阻害剤は、ホルモン依存性疾
患治療に使用することができる。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention found that xanthocillin X and its analogs have aromatase inhibitory activity, and relates to an aromatase inhibitor utilizing this action. The aromatase inhibitor of the present invention can be used for treating hormone-dependent diseases.
【０００２】[0002]
【従来の技術】生体内のエストロジェンは多くの疾患と
関係しており、女性ホルモン依存性疾患である乳癌、子
宮癌、卵巣癌、子宮内膜症、子宮筋腫などがエストロジ
ェンによって症状の増悪が引き起こされる。従って、生
体内のエストロジェン合成酵素であるアロマターゼを阻
害することで生体内エストロジェン量を低下させ、これ
らの疾患を治療する試みが多くなされている。また、い
くつかの男性ホルモン依存性疾患である前立腺肥大症や
前立腺癌などもこのアロマターゼ活性を阻害することで
治療できる。今日までこのアロマターゼ阻害剤に関して
は多くの研究があり、幾多の化合物についてその阻害作
用が調べられてきた。これら阻害剤はその構造から大き
くステロイド系化合物と非ステロイド系化合物に分
けられる。ステロイド系化合物はそのほとんどがアロマ
ターゼ基質であるアンドロステンジオンの誘導体であ
り、また非ステロイド系化合物は複素環化合物のイミダ
ゾール系化合物である。一方、このアロマターゼ阻害剤
を天然物に求める研究はほとんど行われておらず、J.An
tibiotics,44巻、589-599(1991) が知られている程度で
ある。BACKGROUND OF THE INVENTION Estrogen in vivo is associated with many diseases, and estrogen causes exacerbation of symptoms in female hormone-dependent diseases such as breast cancer, uterine cancer, ovarian cancer, endometriosis and uterine fibroids. Be done. Therefore, many attempts have been made to treat these diseases by reducing the amount of estrogen in the living body by inhibiting aromatase which is an estrogen synthase in the living body. In addition, some androgen-dependent diseases such as benign prostatic hyperplasia and prostate cancer can be treated by inhibiting this aromatase activity. To date, there have been many studies on this aromatase inhibitor, and its inhibitory action has been investigated on many compounds. These inhibitors are roughly classified into steroidal compounds and non-steroidal compounds based on their structures. Most of the steroidal compounds are derivatives of androstenedione which is an aromatase substrate, and the non-steroidal compounds are heterocyclic imidazole compounds. On the other hand, almost no research has been conducted on natural products for this aromatase inhibitor.
tibiotics, Volume 44, 589-599 (1991) is known.
【０００３】[0003]
【発明が解決しようとする課題】本発明者らはアロマタ
ーゼ阻害活性を有し、かつ今までにその活性が知られて
いないユニークな構造の化合物をえるべく鋭意探索研究
を行ったところ、意外にも従来公知の抗菌作用を有する
キサントシリンＸ及びその類縁化合物が極めて高いアロ
マターゼ阻害活性を有することを見いだし、この作用を
利用するとホルモン依存性疾患の治療に利用できるとい
う知見を得て、本発明を完成するに至った。本発明のア
ロマターゼ阻害活性を有するキサントシリンＸ及びその
類縁化合物は公知の物質であるが、今回初めてアロマタ
ーゼ阻害活性があることを見いだし、しかも今までに知
られている微生物由来のアロマターゼ阻害活性物質より
も遙かに活性が強く、現在知られている最も強いアロマ
ターゼ阻害剤とほぼ同等の阻害活性を示し、しかも既存
のアロマターゼ阻害剤とは全く異なった構造を示すこと
を見いだした。すなわち、本発明の課題は、活性、体内
での吸収、***、安全性などで有利な新規なアロマター
ゼ阻害剤を提供することにある。さらに、本発明の課題
はアロマターゼ阻害活性を利用して新規なホルモン依存
性疾患治療薬を提供することにある。DISCLOSURE OF THE INVENTION The inventors of the present invention surprisingly conducted a search for a compound having a unique structure which has aromatase inhibitory activity and whose activity has not been known so far, and it was unexpectedly found. Also found that xanthocillin X and its related compounds having a conventionally known antibacterial action have extremely high aromatase inhibitory activity, and obtained the finding that this action can be used for the treatment of hormone-dependent diseases, thus completing the present invention. Came to do. The xanthocillin X having the aromatase inhibitory activity of the present invention and its related compounds are known substances, but this time, it was found for the first time that they have aromatase inhibitory activity, and moreover than the known aromatase inhibitory substances derived from microorganisms. It has been found that it has a much stronger activity, shows almost the same inhibitory activity as the strongest aromatase inhibitors currently known, and has a completely different structure from existing aromatase inhibitors. That is, an object of the present invention is to provide a novel aromatase inhibitor which is advantageous in terms of activity, absorption in the body, excretion, safety and the like. A further object of the present invention is to provide a novel therapeutic drug for hormone-dependent diseases by utilizing the aromatase inhibitory activity.
【０００４】[0004]
【課題を解決するための手段】本発明は次の一般式
（１）で示されるキサントシリンＸ及びその類縁化合物
を有効成分とするアロマターゼ阻害剤に関する。The present invention relates to an aromatase inhibitor containing xanthocillin X represented by the following general formula (1) and its analogs as active ingredients.
【０００５】[0005]
【化２】 （式中、Ｒ1 、Ｒ2 及びＲ3 は、水素、水酸基、硫酸エ
ステル基及び炭素数１から８の直鎖または分岐状のアル
キルオキシ基よりなる群から選択される基を示し、これ
らの基は同一であってもあるいは異なっていてもよ
い。）炭素数１から８の直鎖または分岐状のアルキルオ
キシ基には、メトキシ、エトキシ、プロピオニルオキ
シ、イソプロピオニルオキシ、ブチロキシ、sec-ブチロ
キシ、t-ブチロキシ等の低級アルキルオキシ基、ペンチ
ル、ヘキシル、ヘプチル、オクチル等の直鎖状のアルキ
ルオキシ基あるいはこれらの分岐状のアルキルオキシ基
を例示することができる。また、本発明の有効成分化合
物は、塩酸、燐酸、金属塩等と薬理的に許容される塩を
形成する。本発明の有効成分にはこのような薬理的に許
容される塩となった前記化合物をも包含する。本発明
は、このようなアロマターゼ阻害活性を利用してこの剤
をホルモン依存性疾患治療薬に用いることができる。従
って、前記したように乳癌、子宮癌、卵巣癌、子宮内膜
症、子宮筋腫などの女性ホルモン依存性疾患や前立腺肥
大症、前立腺癌などの男性ホルモン依存性疾患の治療に
用いることができる。[Chemical 2] (In the formula, R 1 , R 2 and R 3 represent a group selected from the group consisting of hydrogen, a hydroxyl group, a sulfuric ester group and a linear or branched alkyloxy group having 1 to 8 carbon atoms; The groups may be the same or different.) The linear or branched alkyloxy group having 1 to 8 carbon atoms includes methoxy, ethoxy, propionyloxy, isopropionyloxy, butyroxy, sec-butyroxy, Examples thereof include lower alkyloxy groups such as t-butyroxy, linear alkyloxy groups such as pentyl, hexyl, heptyl, octyl, and branched alkyloxy groups thereof. Further, the active ingredient compound of the present invention forms a pharmacologically acceptable salt with hydrochloric acid, phosphoric acid, a metal salt and the like. The active ingredient of the present invention also includes the above compound in the form of such a pharmacologically acceptable salt. The present invention can utilize this agent as a therapeutic drug for hormone-dependent diseases by utilizing such aromatase inhibitory activity. Therefore, as described above, it can be used for treating female hormone-dependent diseases such as breast cancer, uterine cancer, ovarian cancer, endometriosis, and uterine fibroids, and androgen-dependent diseases such as benign prostatic hyperplasia and prostate cancer.
【０００６】本発明の式（１）で示される化合物のうち
Ｒ1 、Ｒ2 がそれぞれ水酸基でありＲ3 が水素である化
合物はキサントシリンＸとして、Ｒ1 がメトキシ基、Ｒ
2 が水酸基、Ｒ3 が水素である化合物はキサントシリン
Ｘモノメチルエーテルとして、Ｒ1 及びＲ2 がメトキシ
基、Ｒ3 が水素である化合物はキサントシリンＸジメチ
ルエーテルとして、Ｒ1 、Ｒ2 及びＲ3 がそれぞれメト
キシ基である化合物はキサントシリンＸジメチルエーテ
ルメトキシとして、Ｒ1 がメトキシ基、Ｒ2 が硫酸エス
テル基、Ｒ3 が水素である化合物はキサントシリンＸモ
ノメチルエーテル硫酸エステルとしてそれぞれ公知の化
合物である。これらの化合物は、例えばキサントシリン
Ｘは、ＶＥＢ Arzneimitiel werkDresden 社でBrevicid
の名称で製造されている (Pharmazie 12, 567-580(195
7),The Merck Index 第10版 第9873項) 。また、これ
らの誘導体も従来よく知られている（同上誌) 。さら
に、これらの化合物を、微生物より得る方法としては、
Dichotomomyces albus Saitoを培養して培養液中からキ
サントシリンＸモノメチルエーテルを単離精製する方法
〔J.Antibiotics 21, 587-591(1968) 〕、Aspergillus
sp.(StrainNo.208又はNo.98)を用いてキサントシリンＸ
ジエチルエーテル及びキサントシリンＸジメチルエーテ
ルメトキシを単離する方法〔J.Antibiotics 21, 671-67
9(1968)〕あるいはAspergillus sp. No. FA 2692 を培
養してキサントシリンＸモノメチルエーテル硫酸エステ
ルを単離精製する方法〔J.Antibiotics 46,687-688(199
3)〕等が知られている。従って、この化合物は公知の方
法によって得ることができ、また可能ならば全合成化学
的ないし半合成化学的な製造方法によってつくることが
できる。これらのキサントシリンＸを代表とするキサン
トシリン類は、抗菌作用を有するため抗菌剤、あるいは
抗ウイルス剤、駆虫剤などとして利用できると報告され
ている。Among the compounds represented by the formula (1) of the present invention, the compound in which R 1 and R 2 are hydroxyl groups and R 3 is hydrogen is xanthocillin X, where R 1 is methoxy group and R is
A compound in which 2 is a hydroxyl group and R 3 is hydrogen is xanthocillin X monomethyl ether, a compound in which R 1 and R 2 are methoxy groups, and a compound in which R 3 is hydrogen is xanthocillin X dimethyl ether, and R 1 , R 2 and R 3 are respectively The compound having a methoxy group is known as xanthocillin X dimethyl ether methoxy, and the compound having R 1 as a methoxy group, R 2 is a sulfate ester group, and R 3 is hydrogen is a known compound as xanthocillin X monomethyl ether sulfate. These compounds, such as xanthocillin X, are available from VEB Arzneimitiel werk Dresden in Brevicid.
Manufactured under the name (Pharmazie 12 , 567-580 (195
7), The Merck Index, 10th edition, paragraph 9873). Also, these derivatives are well known in the past (Id.). Furthermore, as a method for obtaining these compounds from microorganisms,
Method for culturing Dichotomomyces albus Saito and isolating and purifying xanthocillin X monomethyl ether [J. Antibiotics 21 , 587-591 (1968)], Aspergillus
Xanthocillin X using sp. (Strain No.208 or No.98)
Method for isolating diethyl ether and xanthocillin X dimethyl ether methoxy [J. Antibiotics 21 , 671-67
9 (1968)] or culturing Aspergillus sp. No. FA 2692 to isolate and purify xanthocillin X monomethyl ether sulfate [J. Antibiotics 46 , 687-688 (199).
3)] etc. are known. Therefore, this compound can be obtained by a known method, and if possible, can be produced by a total synthetic or semi-synthetic chemical production method. It is reported that these xanthocillins typified by xanthocillin X can be used as antibacterial agents, antiviral agents, antiparasitic agents, etc. because they have an antibacterial action.
【０００７】上記アロマターゼ阻害物質のキサントシリ
ンＸ及びその類縁化合物は、常法により錠剤、散剤、カ
プセル剤、顆粒剤、細粒剤、注射剤、吸入剤、または外
用剤等の製剤とすることができ、経口または非経口投与
により抗ホルモン依存性疾患治療薬として臨床に供され
る。投与量は治療するべき症状及び投与方法により左右
されるが、一般的には、成人１日あたり１μg から10ｇ
を１日数回に分けて投与することができる。The above-mentioned aromatase inhibitor xanthocillin X and its analogs can be prepared into tablets, powders, capsules, granules, fine granules, injections, inhalants, or external preparations by a conventional method. , Orally or parenterally, and clinically used as a therapeutic drug for anti-hormone-dependent diseases. The dose depends on the symptoms to be treated and the method of administration, but in general, 1 μg to 10 g per day for an adult
Can be administered in several divided doses per day.
【０００８】前記のように経口投与の製剤形態として
は、錠剤、散剤、カプセル剤、顆粒剤、細粒剤などがあ
り、これらの製剤には賦形剤として、澱粉、乳糖、マン
ニット、エチルセルロース、ナトリウムカルボキシメチ
ルセルロース、ヒドロキシプロピルセルロース等が配合
され、闊沢剤としてステアリン酸マグネシウムまたはス
テアリン酸カルシウムが添加される。一方、ゼラチン、
アラビアゴム、セルロースエステル、ポリビニルピロリ
ドン等が結合剤として用いられる。注射剤、吸入剤、外
用剤等の非経口のための製剤としては無菌の水性または
非水性の溶剤、または乳濁剤があげられる。非水性の溶
液剤または懸濁剤の基剤としてはプロピレングリコー
ル、ポリエチレングリコール、グリセリン、オリーブ
油、とうもろこし油、オレイン酸エチル等が用いられ
る。一方、坐剤の基剤としてはカカオ脂、マクロゴール
等を用いることができる。As mentioned above, the dosage forms for oral administration include tablets, powders, capsules, granules, and fine granules, and these preparations have excipients such as starch, lactose, mannitol, and ethylcellulose. , Sodium carboxymethyl cellulose, hydroxypropyl cellulose and the like are added, and magnesium stearate or calcium stearate is added as a mouthwash. On the other hand, gelatin,
Gum arabic, cellulose ester, polyvinylpyrrolidone and the like are used as the binder. Examples of parenteral preparations such as injections, inhalants, and external preparations include sterile aqueous or non-aqueous solvents or emulsions. As the base of a non-aqueous solution or suspension, propylene glycol, polyethylene glycol, glycerin, olive oil, corn oil, ethyl oleate and the like are used. On the other hand, cacao butter, macrogol and the like can be used as the base of suppositories.
【０００９】次に実施例及び実験例を示し、本発明をさ
らに具体的に説明する。Next, the present invention will be described more specifically by showing Examples and Experimental Examples.
【００１０】[0010]
【実施例１】１錠あたり、キサントシリンＸ10mg、ヒド
ロキシプロピルセルロース30mg、乳糖57mg及びステアリ
ン酸マグネシウム3mg の合計100mg になるように、これ
らの成分及び分量を配合し、この混合物を打錠して製剤
を製造した。[Example 1] Xanthocillin X 10 mg, hydroxypropyl cellulose 30 mg, lactose 57 mg and magnesium stearate 3 mg were combined in a total amount of 100 mg per tablet, and the mixture was tableted to give a formulation. Manufactured.
【００１１】[0011]
【実施例２】本発明のアロマターゼ阻害物質キサントシ
リンＸ及びその類縁化合物は次のような生理活性を有す
る。 アロマターゼ阻害剤 キサントシリンＸ及びその類縁化合物のメタノール溶液
を用いて、アロマターゼ阻害活性は E. A. Thompson ら
の方法 (J. Biol. Chem.,249巻、 5364-5372頁、1974
年) に準じ、ヒト胎盤よりアロマターゼを抽出精製し、
〔１β−3H〕アンドロステンジオンを基質とした酵素活
性測定法における値から阻害率を算出した。阻害率は、
次の式に基づいて算出した。 阻害率（％）＝（１−試験区酵素活性値／対照区酵素活
性値）×100 キサントシリンＸ及びその類縁化合物の上記の方法で得
られる50％アロマターゼ阻害濃度を以下に示した。尚、
活性の比較の為にイミダゾール系のアロマターゼ阻害剤
であるＣＧＳ１６９４９Ａも用いて活性を測定した。こ
のように、ヒト胎盤由来アロマターゼに対する高い阻害
作用はキサントシリンＸ及びその類縁化合物に特有の性
質であると考えられる。Example 2 The aromatase inhibitor xanthocillin X and its related compounds of the present invention have the following physiological activities. The aromatase inhibitory activity of the aromatase inhibitor xanthocillin X and its related compounds in methanol was determined by the method of EA Thompson et al. (J. Biol. Chem., 249, 5364-5372, 1974).
A), extract and purify aromatase from human placenta according to
The inhibition rate was calculated from the value in the enzyme activity measurement method using [1β- 3 H] androstenedione as a substrate. The inhibition rate is
It was calculated based on the following formula. Inhibition rate (%) = (1-test group enzyme activity value / control group enzyme activity value) × 100 The 50% aromatase inhibitory concentration of xanthocillin X and its related compounds obtained by the above method is shown below. still,
For comparison of activity, the activity was also measured using CGS16949A which is an imidazole-based aromatase inhibitor. Thus, it is considered that the high inhibitory effect on human placenta-derived aromatase is a property peculiar to xanthocillin X and its related compounds.
【００１２】 ─────────────────────────────────── 試験化合物 50％アロマターゼ阻害濃度 (μg/ml) ─────────────────────────────────── キサントシリンＸ 0.024 キサントシリンＸモノメチルエーテル 0.054 キサントシリンＸジメチルエーテル 0.024 キサントシリンＸジメチルエーテルメトキシ 0.26 キサントシリンＸモノメチルエーテル硫酸エステル 0.086 ＣＧＳ１６９４９Ａ 0.038 ─────────────────────────────────────────────────────────────────────── Test compound 50% Aromatase inhibitory concentration (μg / ml) ─────────────────────────────────── Xanthocillin X 0.024 Xanthocillin X monomethyl ether 0.054 Xanthocillin X dimethyl ether 0.024 Xanthocillin X dimethyl ether Methoxy 0.26 Xanthocillin X monomethyl ether sulfate 0.086 CGS16949A 0.038 ────────────────────────────────────
【００１３】[0013]
【発明の効果】本発明のキサントシリンＸ及びその類縁
化合物は従来のアロマターゼ阻害剤に無い新しい構造を
有し、アロマターゼ阻害活性の高いものであり、従来の
阻害剤よりも低用量で作用し、ホルモン依存性疾患治療
剤として有用である。INDUSTRIAL APPLICABILITY The xanthocillin X and its analogs of the present invention have a novel structure which is not present in conventional aromatase inhibitors, have high aromatase inhibitory activity, act at a lower dose than conventional inhibitors, and act as hormones. It is useful as a therapeutic agent for addictive diseases.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 吉浜 誠 栃木県宇都宮市江曽島町1400−８ ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Makoto Yoshihama 1400-8 Esojimacho, Utsunomiya City, Tochigi Prefecture
Claims (2)
リンＸ及びその類縁化合物及びその薬理的に許容される
塩を有効成分とするアロマターゼ阻害剤。 【化１】 （式中、Ｒ1 ，Ｒ2 及びＲ3 は、水素、水酸基、硫酸エ
ステル基及び炭素数１から８の直鎖または分岐状のアル
キルオキシ基よりなる群から選択される基を示し、これ
らの基は同一であってもあるいは異なっていてもよ
い。）1. An aromatase inhibitor comprising xanthocillin X represented by the following general formula (1), its analogs and pharmaceutically acceptable salts thereof as active ingredients. [Chemical 1] (In the formula, R 1 , R 2 and R 3 represent a group selected from the group consisting of hydrogen, a hydroxyl group, a sulfuric acid ester group and a linear or branched alkyloxy group having 1 to 8 carbon atoms, The groups may be the same or different.)
疾患を治療する請求項１記載の剤。2. The agent according to claim 1, which treats a hormone-dependent disease by inhibiting aromatase.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23714093A JP2657614B2 (en) | 1993-08-31 | 1993-08-31 | Aromatase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23714093A JP2657614B2 (en) | 1993-08-31 | 1993-08-31 | Aromatase inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0769883A true JPH0769883A (en) | 1995-03-14 |
| JP2657614B2 JP2657614B2 (en) | 1997-09-24 |
Family
ID=17011004
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP23714093A Expired - Lifetime JP2657614B2 (en) | 1993-08-31 | 1993-08-31 | Aromatase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2657614B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265214A (en) * | 2008-05-15 | 2008-09-17 | 中国医学科学院医药生物技术研究所 | Methylophtocillin ester and its salts, and preparation method, application and pharmaceutical composition thereof |
| US7595415B2 (en) | 2005-04-14 | 2009-09-29 | Nissan Chemical Industries, Ltd. | α-Substituted vinyltin compound |
| US7851503B2 (en) | 2002-08-14 | 2010-12-14 | Nissan Chemical Industries, Ltd. | Thrombopoetin receptor activator and process for producing the same |
-
1993
- 1993-08-31 JP JP23714093A patent/JP2657614B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7851503B2 (en) | 2002-08-14 | 2010-12-14 | Nissan Chemical Industries, Ltd. | Thrombopoetin receptor activator and process for producing the same |
| US7595415B2 (en) | 2005-04-14 | 2009-09-29 | Nissan Chemical Industries, Ltd. | α-Substituted vinyltin compound |
| CN101265214A (en) * | 2008-05-15 | 2008-09-17 | 中国医学科学院医药生物技术研究所 | Methylophtocillin ester and its salts, and preparation method, application and pharmaceutical composition thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2657614B2 (en) | 1997-09-24 |
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