JP4620652B2 - 新規ポリガラテノシド化合物およびそれを含む抗鬱剤 - Google Patents
新規ポリガラテノシド化合物およびそれを含む抗鬱剤 Download PDFInfo
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- JP4620652B2 JP4620652B2 JP2006313551A JP2006313551A JP4620652B2 JP 4620652 B2 JP4620652 B2 JP 4620652B2 JP 2006313551 A JP2006313551 A JP 2006313551A JP 2006313551 A JP2006313551 A JP 2006313551A JP 4620652 B2 JP4620652 B2 JP 4620652B2
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- polygalatenoside
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
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- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
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- 208000019906 panic disease Diseases 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 208000024335 physical disease Diseases 0.000 description 1
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- 208000022530 polyphagia Diseases 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 208000012672 seasonal affective disease Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 208000012217 specific developmental disease Diseases 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000016686 tic disease Diseases 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
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- 150000007964 xanthones Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
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- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- Neurology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Description
旋光度は、旋光度測定装置(JASCO DIP−370)を使って測定した。UVスペクトルは、分光光度計(Hitachi UV−3210、日立製作所社製)を使って測定した。IRスペクトルは、KBr disc法で分光光度計(JASCO IR Report−100)を使って測定した。HPLCは、Cosmosil(登録商標)5C−18−MS−IIカラム(20×250mmおよび4.6×250mm、5μm)を用いて、島津製作所社LC−10ATVPシステムにより行った。1H、13C、HMQC、HMBC、およびNOESY NMRは、内部標準としてテトラメチルシラン(TMS)を用いて、Bruker社AMX−400およびVarian−400 Unity PlusNMR分光計で行い、全ての化学シフトの単位は、100万分の1(ppm、δ)である。質量スペクトル(EIまたはFAB)は、VG70−250S分光計で行った。
P.tenuifoliaの根は、2003年5月に台湾台北のマーケットで購入し、C.S.Kuoh教授(国立Cheng Kung大学、生命科学部)によって本物であることが確認された。植物証拠標本(No.920021)は、醫藥工業技術發展中心(台湾、台北市)の標本集に寄託している。
P.tenuifolia(1.25kg)の風乾根を粉末状にし、還流下で2時間、H2O(5L)で2回抽出した。H2O抽出物を、Diaion HP−20カラムクロマトグラフにかけ、H2O(45L)、50%MeOH(30L)、およびMeOH(25L)で連続して溶出させた。50%MeOH溶出液を減圧下濃縮し、淡黄色シロップ(44g)を得、6フラクションとるために、CHCl3/MeOH(80:20、75:25、70:30、65:35、および50:50)と100%メタノールとの混合物を用いてシリカゲルカラム(203〜400メッシュ、E.Merck社、800g)でクロマトグラフを行った。フラクション2(1.0g)を移動相としてH2O/CH3CNの混合物(H2O:CH3CN=70:30、流速:10mL/min;UV230nm)を用いてリサイクル式高性能液体クロマトグラフィー(preparative HPLC)[ODS−5(20×250mm)]にかけ、3つのサブ−フラクション:2−1(125.3mg)、保持時間5〜13分;2−2(121.3mg)、保持時間13〜18分、および2−3(27.1mg)、保持時間18〜23分を得た。サブフラクション2−2をHPLC[カラム:移動相H2O−MeOH(80:20)のODS−5(4.6×250mm);流速:1.0mL/分;UV:230nm]によって分離し、化合物2(保持時間:13.3分)(3.1mg)、化合物5(保持時間:17.7分)(1.6mg)、化合物4(保持時間:19.4分)(3.8mg)、化合物3(保持時間:20.9分)(4.6mg)、および化合物1(保持時間:22.2分)(33.8mg)を得た。それぞれの化合物の構造式は以下の通りである。
無色シロップ様、[α]D+171(c0.01,MeOH);UV(MeOH)λmax(logε)228(4.12),273(3.41),279(sh)(3.37)nm;IR(KBr)νmax3411,1713,1634,1603,1585,1285,1080cm−1;1Hおよび13CNMR,表1および2参照;FABMS m/z 431([M+H]+,3),307(40),291(24),289(18),267(8),154(100),139(11),138(28),137(56),136(58),107(15);HRFABMS m/z 431.1557[M+1]+(calcd for C19H27O11,431.1553)。
無色シロップ様、[α]D+343.1(c0.003,MeOH);UV(MeOH)λmax(logε)228(3.94),272(3.69)nm;IR(KBr)νmax3415,2927,1713,1602,1452,1280cm−1;1Hおよび13CNMR,表1および2参照;FABMS m/z 431[M+H]+,307,291,289,154,137,136,107;HRFABMS m/z 431.1552[M+1]+(calcd for C19H27O11,431.1553)。
無色シロップ様、[α]D+256.6(c0.005,MeOH);UV(MeOH)λmax(logε)229(3.87),273(3.72),301(3.55)nm;IR(KBr)νmax3402,1713,1631,1602,1452,1280cm−1;1Hおよび13CNMR,表1および2参照;FABMS m/z 431([M+H]+,3.4),307(33),291(21),289(15),267(8),155(27),154(100),139(11),138(29),137(57),136(61),107(16);HRFABMS m/z 431.1554[M+1]+(calcd for C19H27O11,431.1553)。
無色シロップ様、[α]D+103.7(c0.004,MeOH);UV(MeOH)λmax(logε)216(3.98),258(4.02)nm;IR(KBr)νmax3414,1708,1606,1512,1464cm−1;1Hおよび13CNMR,表1および2参照;HRFABMS m/z 477.1606[M+1]+(calcd for C20H29O13, 477.1611)。
無色シロップ様、[α]D+616.8(c0.001,MeOH);UV(MeOH)λmax(logε)258(4.15)nm;IR(KBr)νmax3400,1585,1505,1464,1405cm−1;1Hおよび13CNMR,表1および2参照;FABMS m/z 505 ([M+H]+,0.5),503(2),459(3),371(3),369(3),297(4),277(11),241(16),185(100),149(28),117(10),93(98),75(40);HRFABMS m/z 505.1920[M+1]+(calcd for C22H33O13:505.1923)。
ヒトノルエピネフリントランスポーターが安定導入されたイヌ腎臓MDCK細胞由来の膜を用いた。500cm2組織培養プレート中でコンフルエンスに培養された、トランスフェクションされた細胞から、全細胞膜を準備した。細胞を遠心チューブ中に掻き取り、900g、4℃、10分間で沈殿させた。改変したトリス−塩酸緩衝液(50mMトリス−塩酸、100mMNaCl、1μMleupetin、10μMPMSF;pH7.4)で沈殿物を再懸濁し、17000g、4℃、30分間遠心を行った。その後、沈殿物を再懸濁し、テフロンペストルを備えたガラスホモジナイザーでホモジナイズし、17000g、4℃、90分間遠心を行った。沈殿物を回収し、改変したトリス−塩酸緩衝液中に再懸濁した。タンパク質濃度はBCAタンパク質測定試薬(Pierce社,ロックフォード)を用いて定量した。結合アッセイ用に膜タンパク質40μgアリコートを0.2nM[125I]RTI−55(3β−(4−ヨードフェニル)−tropan−2β−カルボン酸メチルエステル)とともに4℃、3時間インキュベートした。0.3%ポリエチレンイミンを浸したWhatman GF/Bを使って急速真空濾過し、冷バッファー1mLで3回急速で洗うことによって結合を止めた。ガンマ線分光分析によって結合した放射活性を測定した。非特異性の結合は、10μMデシプラミン存在下で測定し、特異的結合を算出するためにデシプラミン非存在下のデータから、非特異性結合を差し引いた。
P.tenuifolia(1.25kg)の風乾根を粉末状にし、還流下、水で抽出した。H2O抽出物は、Diaion HP−20カラムクロマトグラフにかけ、順にH2O、50%MeOH、および100%MeOHで溶出した。6フラクションとるために、CHCl3/MeOHを用いてシリカゲルカラム上で50%MeOH溶出液をクロマトグラフにかけた。得られたもののうち、フラクション2が濃度依存的にMDCK細胞のノルエピネフリントランスポーターに対する[125I]RTI−55を阻害した。IC50値は、4.6μg/mLであった。次にフラクション2を逆相ODSカラムを用いたリサイクル式高性能液体クロマトグラフィー(preparative HPLC)にかけ、5つの新規オリゴ糖誘導体ポリガラテノシドA〜E(化合物1〜5)を得た。
Claims (5)
- 下記化学式(1):
- 前記R2が水素原子である請求項1に記載の化合物またはその薬剤として許容される塩。
- 前記R、R’、R”のいずれか1つがR1であり、その他2つが水素原子である、請求項2に記載の化合物またはその薬剤として許容される塩。
- 薬剤的に許容できるキャリアーおよび希釈剤とともにノルエピネフリン輸送遮断によるノルエピネフリンの再取り込み阻害剤として請求項1〜3のいずれか1項に記載の化合物またはその薬剤として許容される塩を含む、ノルエピネフリンの再取り込み阻害が有効な疾病用薬剤組成物。
- 前記疾病が嗜癖障害、禁断症候群、適応障害、加齢性の学習障害や精神障害、拒食症、無気力、注意力欠如障害、注意力欠陥多動性障害(ADHD)、双極性障害、または肥満である請求項4に記載の薬剤組成物。
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