JP5718233B2 - 甲状腺刺激ホルモン受容体(tshr)の低分子量アゴニスト - Google Patents
甲状腺刺激ホルモン受容体(tshr)の低分子量アゴニスト Download PDFInfo
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- JP5718233B2 JP5718233B2 JP2011532048A JP2011532048A JP5718233B2 JP 5718233 B2 JP5718233 B2 JP 5718233B2 JP 2011532048 A JP2011532048 A JP 2011532048A JP 2011532048 A JP2011532048 A JP 2011532048A JP 5718233 B2 JP5718233 B2 JP 5718233B2
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- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 208000013076 thyroid tumor Diseases 0.000 description 1
- 108040006218 thyroid-stimulating hormone receptor activity proteins Proteins 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Description
式中のR1からR4は、それぞれ独立してH、ヒドロキシル、アルキル、アルコキシ、アミノカルボニルまたはハロゲンであり;
R5は、H、アルキル、アリール、アラルキルまたはアミノカルボニルであり;
Aは、-N=C(R15)-(左端の結合手が上記式Iのベンゼン環に結合し、右端の結合手が上記式Iのヘテロ原子窒素に結合する)または-NH-CH(R15)-(左端の結合手が上記式Iのベンゼン環に結合し、右端の結合手が上記式Iのヘテロ原子窒素に結合する)を表し;
R15は、次式IIで表され:
R10からR14は、それぞれ独立してH、ヒドロキシル、アルキル、アルコキシまたはアミノカルボニルであり;
Xは、O、SまたはN(H)であり;
但し、式Iの化合物が下記の化合物1でないことを条件とする。
R21は、アリールまたはヘテロアリールであり;
R22は、請求項1に示す式IIのR15、ヘテロアリールまたはアリールである。
R5は、H、アルキル、アリール、アラルキルまたはアミノカルボニルであり;
Aは、-N=C(R15)-(左端の結合手が上記式Iのベンゼン環に結合し、右端の結合手が上記式Iのヘテロ原子窒素に結合する)または-NH-CH(R15)-(左端の結合手が上記式Iのベンゼン環に結合し、右端の結合手が上記式Iのヘテロ原子窒素に結合する)を表し;
R15は、次式IIで表され:
R10からR14は、それぞれ独立してH、ヒドロキシル、アルキル、アルコキシまたはアミノカルボニルであり;
Xは、O、SまたはN(H)である;
の化合物の少なくとも一つ若しくはその薬学的に許容し得る塩か、
または式VIの化合物の少なくとも一つを被検体に投与することを備える。
本明細書に開示するのは、TSHRを活性化する低分子量(例えば、1000ダルトン未満)の化合物である。これらの化合物は、経口投与し得る。データを以下に示し、ヒトTSHR発現株細胞における化合物の効能を実証する。本明細書に開示した特定の化合物は、TSHRに対する選択的アゴニストである(すなわち、該化合物は他のホルモン受容体、特にLHCGRおよびFSHRを活性化または調節しない)。化合物はまた、TSHRに対する完全フルアゴニストでもあり得る。
式中のR1-R4はそれぞれ独立してH、ヒドロキシル、アルキル、アルコキシ、アミノカルボニルまたはハロゲンであり;
R5はH、アルキル、アリール、アラルキルまたはアミノカルボニルであり;
Aは-N=C(R15)-(左端の結合手が上記式Iのベンゼン環に結合し、右端の結合手が上記式Iのヘテロ原子窒素に結合する)または-NH-CH(R15)-(左端の結合手が上記式Iのベンゼン環に結合し、右端の結合手が上記式Iのヘテロ原子窒素に結合する)を表し;
R15は次式IIで表され:
R10-R14はそれぞれ独立してH、ヒドロキシル、アルキル、アルコキシまたはアミノカルボニルであり;
XはO、SまたはN(H)である。
本明細書に開示した化合物は、通常下記のように合成することができる。スキーム1を参照するに、2-アミノベンズアミド(1)を種々のアミンでの2-アミノ安息香酸のアミドカップリング(ステップi)またはアミンとイサト酸無水物との反応(ステップii)のいずれかにより調製した。
本明細書に開示した化合物は、甲状腺ガンスクリーニング、甲状腺ガンの治療、結節性甲状腺腫の治療、PETスキャニングおよび化学療法治療を増強するためのTSH刺激、先天性甲状腺機能低下症の鑑別診断、骨粗しょう症の治療(例えば、骨量減少の抑制)および過体重または肥満の治療(例えば、脂肪組織の代謝率の増加)に有用である。本明細書に開示した化合物の実例的使用は以下の通りである:
サイログロブリン(Tg)のアゴニスト試験を甲状腺抑制治療中の未検出Tgを有する患者に用いて残存または再発甲状腺ガンの診断を排除することができる;
アゴニスト治療を放射性ヨウ素(131I)と組み合わせて用い、転移性疾患の所見がない患者の甲状腺全摘術に続いて甲状腺残部を切除することができる;
アゴニスト試験を、甲状腺ホルモン禁断試験を受ける意志がなく、かつ治療医がより低感度なテストの使用が理に叶うと考えている患者であって、血清Tgテストおよび放射性ヨウ素イメージングを必要とする患者に用いることができる;または
アゴニスト治療および試験を、甲状腺ホルモン禁断に対して適切な内在性TSH反応を示すことができないか、または禁断を医学的に禁忌とされる患者に用いることができる。
全ての市販の試薬および溶媒を購入し、更なる精製なく用いた。全てのマイクロ波反応を、磁気攪拌棒を備えた密封マイクロ波バイアル中で行い、Biotage Initiator Microwave Synthesizer中で加熱した。生物学的試験用の全ての化合物を、Phenomenex Luna(登録商標) C18逆相(5ミクロン、30×75 mm)カラムを備えた半分取HPLCを流速45 mL/分で用いて精製した。移動相は、各々0.1%のトリフルオロ酢酸を含有するアセトニトリルおよびH2Oの混合物であった。精製の間、30%〜80%勾配のアセトニトリルを8分間に渡ってUV検出(220 nM)により誘発される画分収集を伴って用いた。純粋な画分をPL-HCO3 MP SPE (Varian)に通してトリフルオロ酢酸を除去し、真空下凍結乾燥機で濃縮した。1Hスペクトルを、Inova 400(100) MHzスペクトロメーター(Varian)を用いて記録した。化学シフトを、内部標準としてのCDCl3(7.27)中の1H(残余の)を用いてδ(ppm)単位で報告する。データを以下の通りに報告する:化学シフト、多重度(s = シングレット、d = ダブレット、t = トリプレット、q = カルテット、m = マルチプレット、br = ブロード)、カップリング定数および積分値。サンプルを、Zorbax(商標) Eclipse XDB-C18逆相(5ミクロン、4.6×150 mm)カラムを備えたAgilent 1200 series LC/MSにおいて流速1.1 mL/分で純度について分析した。移動相は、各々0.05%のトリフルオロ酢酸を含有するアセトニトリルおよびH2Oの混合物とした。分析の間、5%〜100%勾配のアセトニトリルを8分間に渡って用いた。高分解能マススペクトル測定をAgilent 6210 Electrospray TOF mass spectrometerで行った。
以下の一般的な手順を用いて、異なるが類似する構造を有する化合物を合成した。当業者は、所要に応じて所望の転移を達成するためにこれら一般的な手法を修正する方法を認識するであろう。
イサト酸無水物(0.163 g、1.0 mmol、1.0当量)の10 mL無水アセトニトリル溶液にアミン(1.05 mmol、1.05当量)を室温で加えた。生成した混合物を室温で2時間撹拌し、50℃で4時間加熱した。その後、真空で濃縮し、固体としての生成物を90-99%の収率で得た。
1.5 mLの無水DMAにおける3-(クロロメチル)-4-メトキシベンズアルデヒド(300 μmol, 1.0 当量)および適切に置換されたフェノールまたはチオフェノール(360 μmol, 1.2当量)の溶液にK2CO3(1.5 mmol, 5当量)を加えた。混合物をマイクロ波シンセサイザ中150℃で10分間加熱した。固体を濾過した。透明な溶液に2-アミノベンズアミド(1.2当量)添加し、その後トリフルオロメタンスルホン酸イッテルビウム(150 μmol, 0.5当量)を加えた。混合物をマイクロ波シンセサイザ中200℃で10分間加熱して、所望の2, 3-ジヒドロキナゾリン-4-オンを得た。DDQ(300 μmol, 1.5 Mアセトニトリル溶液, 1.0当量)溶液を、2, 3-ジヒドロキナゾリン-4-オンを含む反応混合物に加え、生成した混合物を1時間撹拌してキナゾリン-4-オンを得た。全ての粗生成物をHPLCにより精製した。PL-HCO3 MP SPEを用いてTFAを除去した。最終生成物を20-50%の収率で固体として得た。
ヒトTSHRのcDNAをhTSHR-pSVL(1)からPCRにより増幅し、制限酵素サイトXhoIおよびBamHIを用いてpcDNA3.1(-)/ハイグロマイシンベクターに挿入した。ヒトLHCGRのcDNAをhLHR-pGS5(2)からPCRにより増幅し、制限酵素サイトBamHIおよびXhoIを用いてpcDNA3.1(+)/ハイグロマイシンベクターに挿入した。pcDNA3.1に組み込まれたFSHRcDNAを、Missouri S&T cDNA Resource Center (www.cDNA.org) から入手し、pcDNA3.1(-)/ハイグロマイシンベクターにサブクローニングした。構築物をシーケンシング(MWG Biotech)により確認した。FuGENE 6 Transfection試薬(Roche Diagnostics)を用いて製造業者のプロトコルに従ってHEK-EM293細胞をTSHR、LHCGRまたはFSHRのcDNAでトランスフェクトした。トランスフェクションの2日後に、細胞を10%のウシ胎児血清、100 unit/mlのペニシリンおよび100 g/mlのストレプトマイシン(Life Technologies Inc.)、および選択マーカーとしてハイグロマイシン(250μg/ml)が追加されたDulbecco's modified Eagle's Medium (DMEM) に通し、生育させた。7〜10日後にハイグロマイシン耐性クローンを選択し、更なる生育の2、3日後にcAMPアッセイに供して、適切な受容体を安定発現するクローンを同定した。
TSHR、LHCGRまたはFSHRを安定発現する細胞、およびHEK293の親細胞を、10% FBS, 100 units/ml ペニシリン, 100μg/mlストレプトマイシンを含有するDMEM培地中に5%CO2、37℃で維持した。TSHR、LHCGRまたはFSHRを安定発現する細胞については、追加の250μg/mlのハイグロマイシンを細胞培養中に加えた。細胞を、35 mlの培地を含むT175フラスコ中に300万〜400万個の細胞の密度で播種し、3日間生育させて80-90%コンフルエントとした。この密度でのHEK293細胞のフラスコには、概して合計3000万個の細胞が得られた。
化合物を、TSHR細胞株および親細胞株の両方に対してHTRF cAMP検出キット(Cisbio, Bedford, MA)を用いて分析した。簡潔には、750個の細胞を、1536ウェル平底白色プレート中の2.5 μl/ウェルの完全培地(10%FCSを含むDMEM)中に播種し、DMSO溶液中の化合物またはコントロールを20 nl/ウェルで加えた。室温で30分の培養後、2.5 μl/ウェルの標識化d2cAMPおよび2.5 μl/ウェルの抗-cAMP抗体(いずれも溶解バッファ中に1:20で希釈)を各ウェルに飛翔試薬ディスペンサー(Aurora Discovery, San Diego)を使用して加えた。プレートを330ナノメートルの励起および615ナノメートルおよび660ナノメートルの発光でEnvision plate reader(PerkinElmer, Boston, MA)を使用して測定した。
化合物を384-ウェルプレートにおいてDMSOで1:5または1:2.236に連続希釈して、7または15の濃度(最小限には、10mM、2mM、0.4mM、80μM、16μM、3.2μMおよび0.64μM)を得、1,536-ウェルプレートに7 μl/ウェルで合わせた。細胞培養中の最終化合物濃度は、1.60nMから25.0μMの範囲とした。
最大応答(100%の活性)を30 mU/mlのTSHの応答により決定し、基礎応答(0%の活性)をTSHスクリーン中のDMSOコントロールにより測定した。化合物のEC50の値は、Prism software (GraphPad Software, San Diego, CA)を用いる非線形回帰分析法による濃度反応曲線から算出した。
50,000細胞/ウェルを96ウェルプレート中の完全培地(10%FCSを含むDMEM)に播種した。細胞を24時間培養した後に、5%CO2の加湿培養器において1 mMの3-イソブチル-1-メチルキサンチン(IBMX) (SIGMA)およびウシTSH(1.8 μM)またはヒトLHもしくはFSH (1000 ng/ml)または化合物 (0.01μM-100μM)を含む無血清DMEM中で37℃で1時間培養した。化合物での培養後に培地を吸引した後、細胞をcAMP-Screen DirectTM System (Applied Biosystems, Cat # CSD200)の溶解バッファを用いて洗浄した。細胞溶解物のcAMP含有量は、製造業者のプロトコルを用いて決定した。効能(EC50)を、Windows(登録商標)版GraphPad Prism 4でのデータ分析により投与量反応曲線(化合物0-100μM)から得た。
化合物3が590nM
化合物3/4が25nM
化合物3/5が38nM
化合物3/1が100nM
化合物3/2が541nMである。
甲状腺細胞組織のサンプルを、無関係な理由による手術中に、National Institutes of Health Clinical Centerから得た。患者は、IRB 承認プロトコルに対しインフォームドコンセントを提供し、またOffice of Human Subjects Researchを介して研究活動の承認を経て匿名で材料を受領した。試料を氷上のHBSS中に維持し、細胞の単離を手術後4時間以内に開始した。全ての調製を、無菌条件下で行った。組織サンプルは、少量のHBSSを用いて10cmディッシュ中で微細な外科用鉗子およびハサミにより小片に細分化した。組織片を15mlのチューブ(Falcon) に移し、HBSSで少なくとも3回洗浄した。その後、組織片を3 mg/mlのCollagenase Type IV(Gibco)を含むHBSSを用いて培養した。単離した細胞の懸濁液が得られるまで、37℃の水浴中で一定の振盪で30分間以上酵素消化を行った。1000rpmで5分間遠心分離した後、上澄みを除去し、細胞を10%のFBSを有する10 mlのDMEM中に再懸濁した。細胞を10cmの組織培養ディッシュに播種し、5%CO2の加湿培養器において37℃で培養した。24時間後、非接着細胞を含む上澄みを除去した。甲状腺細胞の初代培養は、5-7日以内にコンフルエントな単層を形成した。サイログロブリンおよびサイロペルオキシダーゼのmRNA発現を定量するために、実験の24時間前に、甲状腺細胞を6×104細胞/ウェルの密度で24-ウェルプレートに播種した。
全RNAを、RNeasy Micro kits (Qiagen)を用いて精製した。一本鎖cDNAを、High Capacity cDNA Archive Kit (Applied Biosystems)を用いて調製した。RT-PCRを、100 ngの全RNAおよびUniversal PCR Master Mix (Applied Biosystems)から調製したcDNAを用いる25μlの反応中で行った。サイログロブリンおよびサイロペルオキシダーゼ用のプライマーおよびプローブは、Assay-on-Demand (Applied Biosystems)とした。定量RT-PCRの結果を、RNA量の差異に関して補正するために、GAPDHについて規格化した。
Claims (35)
- 次式I:
R5はH、アルキル、アラルキルまたはアミノカルボニルであり;
Aは−N=C(R15)−(左端の結合手が上記式Iのベンゼン環に結合し、右端の結合手が上記式Iのヘテロ原子窒素に結合する)または−NH−CH(R15)−(左端の結合手が上記式Iのベンゼン環に結合し、右端の結合手が上記式Iのヘテロ原子窒素に結合する)を表し;
R15は次式IIで表され:
R10−R14はそれぞれ独立してH、ヒドロキシル、アルキル、アルコキシまたはアミノカルボニルであり;
XはO、SまたはN(H)であり;
但し、式Iの化合物が次式
;
(化合物 3/2)
(構造2)
;
(化合物 3/3)
(構造17)
;及び
(構造162)
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
;及び
を除く)で表される化合物またはその薬学的に許容し得る塩。 - 前記R1−R4はそれぞれ独立してH、ヒドロキシルまたはアセトアミドであり;
R5はアラルキルであり;
R6、R7、R8、R10、R11、R13およびR14はそれぞれHであり;
R9はアルコキシであり;
R12はアセトアミドであり;そして、
XはOまたはSである請求項1に記載の化合物。 - 前記R5が
- 前記R9がC1−C4のアルコキシである請求項1〜3のいずれか一項に記載の化合物。
- 前記XがOである請求項1〜4のいずれか一項に記載の化合物。
- 前記R15が次式III:
- 化合物が:
- 化合物が:
- 化合物が甲状腺刺激ホルモン受容体アゴニストである請求項1〜8のいずれか一項に記載の化合物。
- R12はアミノカルボニルである請求項1〜5、9のいずれか一項に記載の化合物。
- R4はヒドロキシルであり;
R5はアラルキルであり;
R9はC1〜C4アルコキシであり;
R12はアミノカルボニルであり;
XはOである請求項1または10に記載の化合物。 - R12は-N(R)−C(O)−Rであり、式中、Rはアルキルである請求項1〜5、9のいずれか一項に記載の化合物。
- R4はヒドロキシルであり;
R5はアラルキルであり;
R9はC1〜C4アルコキシであり; R12は-N(R)−C(O)−Rであり、式中、Rはアルキルであり;
XはOである請求項1または9に記載の化合物。 - 化合物が:
- 診断学的に有効な量の請求項1〜14のいずれか一項に記載の化合物またはその薬学的に許容し得る塩を含む甲状腺ガン検出用の薬剤。
- 治療学的に有効な量の請求項1〜14のいずれか一項に記載の化合物またはその薬学的に許容し得る塩を含む骨変性障害の治療用または予防用の薬剤。
- 治療学的に有効量の請求項1〜14のいずれか一項に記載の化合物またはその薬学的に許容し得る塩を含む甲状腺ガン治療用の薬剤。
- 転移性疾患の所見がない被検体の甲状腺全摘術に続いて甲状腺残部を切除するために式Iの化合物と同時投与される放射性ヨウ素を更に含む請求項17に記載の薬剤。
- 請求項1〜14のいずれか一項に記載の化合物またはその薬学的に許容し得る塩を含む甲状腺刺激ホルモン受容体活性化用の薬剤。
- 前記化合物が経口投与される請求項15〜19のいずれか一項に記載の薬剤。
- 前記式Iの化合物において、
R1−R4はそれぞれ独立してH、ヒドロキシルまたはアセトアミドであり;
R5はアラルキルであり;
R6、R7、R8、R10、R11、R13およびR14はそれぞれHであり;
R9はアルコキシであり;
R12はアセトアミドである請求項15〜20のいずれか一項に記載の薬剤。 - 前記式Iの化合物において、
R5が
- 前記式Iの化合物において、R9がC1−C4のアルコキシである請求項15〜22のいずれか一項に記載の薬剤。
- 前記式Iの化合物において、XはOである請求項15〜23のいずれか一項に記載の薬剤。
- 前記式Iの化合物が
- 前記式Iの化合物が
- 前記式Iの化合物が
- 前記式Iの化合物が
- 前記式Iの化合物において、R15が次式III:
- 前記式Iの化合物が被検体に投与される請求項15〜29のいずれか一項に記載の薬剤。
- 請求項1〜14のいずれか一項に記載の化合物の少なくとも一つと、薬学的に許容し得る担体とを含む製薬学的組成物。
- R12はアミノカルボニルである請求項15〜20のいずれか一項に記載の薬剤。
- R4はヒドロキシルであり;
R5はアラルキルであり;
R9はC1〜C4アルコキシであり;
R12はアミノカルボニルであり;
XはOである請求項15〜20のいずれか一項に記載の薬剤。 - R12は−N(R)−C(O)−Rであり、式中、Rはアルキルである請求項15〜20のいずれか一項に記載の薬剤。
- R4はヒドロキシルであり;
R5はアラルキルであり;
R9はC1〜C4アルコキシであり; R12は−N(R)−C(O)−Rであり、式中、Rはアルキルであり;
XはOである請求項15〜20のいずれか一項に記載の薬剤。
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