JP6081528B2 - イソチアゾロピリミジノンを用いた神経形成を刺激するためおよびニューロン変性を阻害するための方法および組成物 - Google Patents
イソチアゾロピリミジノンを用いた神経形成を刺激するためおよびニューロン変性を阻害するための方法および組成物 Download PDFInfo
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 229940073585 tromethamine hydrochloride Drugs 0.000 description 1
- 230000004143 urea cycle Effects 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000010044 viral meningitis Diseases 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- MJIBOYFUEIDNPI-HBNMXAOGSA-L zinc 5-[2,3-dihydroxy-5-[(2R,3R,4S,5R,6S)-4,5,6-tris[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoyl]oxy]-2-[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoyl]oxymethyl]oxan-3-yl]oxycarbonylphenoxy]carbonyl-3-hydroxybenzene-1,2-diolate Chemical class [Zn++].Oc1cc(cc(O)c1O)C(=O)Oc1cc(cc(O)c1O)C(=O)OC[C@H]1O[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H]1OC(=O)c1cc(O)c(O)c(OC(=O)c2cc(O)c([O-])c([O-])c2)c1 MJIBOYFUEIDNPI-HBNMXAOGSA-L 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
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Description
本出願は、2007年6月21日に出願された米国仮出願第60/945,524号の優先権を主張する。
本発明は、概して神経学の分野に関する。より具体的には、本発明は、神経形成を刺激するためおよびニューロン変性を阻害するための方法および組成物を提供する。
アルツハイマー病は、ニューロンを徐々に破壊する脳の障害である。アメリカにおいて450万人を超える人々がアルツハイマー病に罹患しており、ほとんどが高齢者に起こっている。アルツハイマー病を発症するリスクは、年齢65歳を過ぎると5年毎にほぼ倍加して、85歳までに50%に達する。アルツハイマー病に罹患した患者は、学習、記憶、論理的思考、判断、意思疎通、および日常活動を行う能力を失う。アルツハイマー病患者の看護に関する直接的および間接的な費用は、毎年少なくとも1兆ドルまで増加した。
式中、
R1は、水素、アルキル、分岐アルキル、アリール、アラルキル、ベンジル、ナフチル、炭素原子1〜12個のシクロアルキル、または複素環であり、R1が水素ではない場合それはH、OH、アルキル、アルコキシ、ハロゲン、-CF3、-R2、-OR2、-SR2、-N(R2)2、-CN、-NO2、-NC(O)R2、-C(O)R2、-C(O)N(R2)2、-S(O)2R2、-S(O)2NR2、-S(O)R2、-C(O)R2、-C(O)OR2、または-C(O)N(R2)2で置換されていてもよく、式中、各R2は独立して、H、アルキル、アルケニル、アルキニル、アリール、複素環、保護基、またはプロドラッグ部分であり;
Lは、[CH2]2-6、-CH2-(C=O)-CH2-、
であり;
Xは、S、SO2、O、またはNHであり;
Yは、
であり;
Zは、それぞれH、OH、アルキル、アルコキシ、ハロゲン、または-CF3で置換されていてもよい
であり;
Tは、O、S、またはNR1であり;
nは2または3であり;
式中、各R1は独立しており、かつ互いに同じであってもよく、または好ましくは異なっていてもよい。
[本発明1001]
下記式Iに従う構造を有する化合物:
式中、
R1は、水素、アルキル、分岐アルキル、アリール、アラルキル、ベンジル、ナフチル、炭素原子1〜12個のシクロアルキル、または複素環であり、R1が水素ではない場合それはH、OH、アルキル、アルコキシ、ハロゲン、-CF3、-R2、-OR2、-SR2、-N(R2)2、-CN、-NO2、-NC(O)R2、-C(O)R2、-C(O)N(R2)2、-S(O)2R2、-S(O)2NR2、-S(O)R2、-C(O)R2、C(O)OR2、または-C(O)N(R2)2で置換されていてもよく、式中、各R2は独立して、H、アルキル、アルケニル、アルキニル、アリール、複素環、保護基、またはプロドラッグ部分であり;
Lは、[CH2]2-6、-CH2-(C=O)-CH2-、
であり;
Xは、S、SO2、O、またはNHであり;
Yは、
であり;
Zは、それぞれH、OH、アルキル、アルコキシ、ハロゲン、または-CF3で置換されていてもよい
であり;
Tは、O、S、またはNR1であり;
nは2または3であり;
式中、各R1は独立しており、かつ互いに同じであってもよく、または好ましくは異なっていてもよい。
[本発明1002]
、およびその薬学的に許容される塩、水和物、または溶媒和物からなる群より選択される、本発明1001の化合物。
[本発明1003]
下記式の化合物および薬学的に許容される賦形剤または担体を含む、薬学的組成物:
式中、
R1は、水素、アルキル、分岐アルキル、アリール、アラルキル、ベンジル、ナフチル、炭素原子1〜12個のシクロアルキル、または複素環であり、R1が水素ではない場合それはH、OH、アルキル、アルコキシ、ハロゲン、-CF3、-R2、-OR2、-SR2、-N(R2)2、-CN、-NO2、-NC(O)R2、-C(O)R2、-C(O)N(R2)2、-S(O)2R2、-S(O)2NR2、-S(O)R2、-C(O)R2、C(O)OR2、または-C(O)N(R2)2で置換されていてもよく、式中、各R2は独立して、H、アルキル、アルケニル、アルキニル、アリール、複素環、保護基、またはプロドラッグ部分であり;
Lは、[CH2]2-6、-CH2-(C=O)-CH2-、
であり;
Xは、S、SO2、O、またはNHであり;
Yは、
であり;
Zは、それぞれH、OH、アルキル、アルコキシ、ハロゲン、または-CF3で置換されていてもよい
であり;
Tは、O、S、またはNR1であり;
nは2または3であり;
式中、各R1は独立しており、かつ互いに同じであってもよく、または好ましくは異なっていてもよい。
[本発明1004]
前記化合物が、
、およびその薬学的に許容される塩、水和物、または溶媒和物からなる群より選択される、本発明1003の薬学的組成物。
[本発明1005]
哺乳動物において神経形成を刺激するためおよび/またはニューロン変性を阻害するために有効な量で薬学的組成物を投与する段階を含む、哺乳動物において神経形成を刺激するためおよび/またはニューロン変性を阻害するための方法であって、薬学的組成物が以下を含む、方法:
式中、
R1は、水素、アルキル、分岐アルキル、アリール、アラルキル、ベンジル、ナフチル、炭素原子1〜12個のシクロアルキル、または複素環であり、R1が水素ではない場合それはH、OH、アルキル、アルコキシ、ハロゲン、-CF3、-R2、-OR2、-SR2、-N(R2)2、-CN、-NO2、-NC(O)R2、-C(O)R2、-C(O)N(R2)2、-S(O)2R2、-S(O)2NR2、-S(O)R2、-C(O)R2、C(O)OR2、または-C(O)N(R2)2で置換されていてもよく、式中、各R2は独立して、H、アルキル、アルケニル、アルキニル、アリール、複素環、保護基、またはプロドラッグ部分であり;
Lは、[CH2]2-6、-CH2-(C=O)-CH2-、
であり;
Xは、S、SO2、O、またはNHであり;
Yは、
であり;
Zは、それぞれH、OH、アルキル、アルコキシ、ハロゲン、または-CF3で置換されていてもよい
であり;
Tは、O、S、またはNR1であり;
nは2または3であり;
式中、各R1は独立しており、かつ互いに同じであってもよく、または好ましくは異なっていてもよい。
[本発明1006]
哺乳動物がヒトである、本発明1005の方法。
[本発明1007]
ヒトが、神経変性疾患、脳損傷、神経損傷、精神障害、および加齢より選択される状態を患っている患者である、本発明1006の方法。
[本発明1008]
哺乳動物において神経形成を刺激するためおよび/またはニューロン変性を阻害するために有効な量で薬学的組成物を投与する段階を含む、哺乳動物において神経形成を刺激するためおよび/またはニューロン変性を阻害するための方法であって、薬学的組成物が
、およびその薬学的に許容される塩、水和物、または溶媒和物からなる群より選択される化合物を含む、方法。
本明細書に記載の特定の方法論、アッセイ等は変化する可能性があることから、本発明は、これらに限定されないと理解される。同様に、本明細書において用いる用語は本発明の例示的な局面を記載する目的のために用いられ、本発明の範囲を制限すると意図されないと理解される。
本明細書において用いられるように、「化合物」という用語は、本明細書に開示の構造および式に関する全ての反復を指し、同様に生理的に許容されるその塩に対する参照が含まれる。本発明の化合物の生理的に許容される塩の例には、ナトリウムのようなアルカリ金属、マグネシウムのようなアルカリ土類、アンモニウム、およびNX4 +(式中XはC1〜C4アルキルである)のような適当な塩基に由来する塩が含まれる。水素原子またはアミノ基の生理的に許容される塩には、酢酸、安息香酸、乳酸、フマル酸、酒石酸、マレイン酸、マロン酸、リンゴ酸、イセチオン酸、ラクトビオン酸、およびコハク酸のような有機カルボン酸塩;メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、およびp-トルエンスルホン酸のような有機スルホン酸;ならびに塩酸、硫酸、リン酸、およびスルファミン酸のような無機酸の塩が含まれるがこれらに限定されるわけではない。ヒドロキシ基の化合物の生理的に許容される塩には、Na+およびNX4 +(XはHまたはC1〜C4アルキル基から独立して選択される)のような適した陽イオンと組み合わせた化合物の陰イオンが含まれるが、これらに限定されるわけではない。
1つの局面において、本発明は、以下の構造を有する化合物を含む組成物を含む:
式中、
R1は、水素、アルキル、分岐アルキル、アリール、アラルキル、ベンジル、ナフチル、炭素原子1〜12個のシクロアルキル、または複素環であり、R1が水素ではない場合それはH、OH、アルキル、アルコキシ、ハロゲン、-CF3、-R2、-OR2、-SR2、-N(R2)2、-CN、-NO2、-NC(O)R2、-C(O)R2、-C(O)N(R2)2、-S(O)2R2、-S(O)2NR2、-S(O)R2、-C(O)R2、-C(O)OR2、または-C(O)N(R2)2で置換されていてもよく、式中、各R2は独立して、H、アルキル、アルケニル、アルキニル、アリール、複素環、保護基、またはプロドラッグ部分であり;
Lは、[CH2]2-6、-CH2-(C=O)-CH2-、
であり;
Xは、S、SO2、O、またはNHであり;
Yは、
であり;
Zは、それぞれH、OH、アルキル、アルコキシ、ハロゲン、または-CF3で置換されていてもよい
であり;
Tは、O、S、またはNR1であり;
nは2または3であり;
式中、各R1は独立しており、かつ互いに同じであってもよく、または好ましくは異なっていてもよい。
本発明はまた、本明細書に開示の化合物を含む薬学的組成物を含む。化合物を含む薬学的組成物の有効量の投与経路および用量も同様に開示される。本発明の化合物は、疾患の有効な処置のための多様なプロトコールにおいて他の薬剤と併用して投与することができる。
本発明はさらに、経口、非経口、皮下、筋肉内、静脈内、関節内、気管支内、腹腔内、嚢内、軟骨内、腔内、体腔内、小脳内、脳室内、結腸内、頚管内、胃内、肝臓内、心筋内、骨内、骨盤内、心膜内、腹腔内、胸膜腔内、前立腺内、肺内、腎臓内、網膜内、脊髄内、滑液包内、胸腔内、子宮内、膀胱内、ボーラス、膣内、直腸内、口腔内、舌下、鼻腔内、イオン導入手段、または経皮手段が含まれるがこれらに限定されるわけではない経路による、本明細書に開示の少なくとも1つの化合物の投与に関する。
活性成分の特定の量を有する様々な薬学的組成物を調製する方法は公知であるか、または本開示に照らして当業者に明らかであると考えられる。該薬学的組成物を調製する方法は、REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995)において記載されるように、他の適した薬学的賦形剤およびその製剤を組み入れることができる。
一般的に、本明細書に開示の化合物は、任意の可能性がある毒性を最小限にしながら最適な有効性を得るためにルーチン試験によって定義される適当な用量で、単独で、または他の治療物質と共に用いてもよい。本発明の化合物を利用する投与レジメンは、患者のタイプ、種、年齢、体重、性別、病状;処置される状態の重症度;投与経路;患者の腎機能および肝機能;ならびに用いられる特定の化合物を含む多様な要因に従って選択してもよい。当業者の医師または獣医師は、状態を予防する、抵抗する、または進行を停止させるために必要な薬物の有効量を容易に決定および処方することができる。
もう1つの局面において、本発明はさらに、ニューロンの喪失に関連する任意の疾患の処置において有用性を有する方法に向けられる。より具体的に、本発明はさらに、哺乳動物において神経形成を刺激するためおよび/またはニューロン変性を阻害するための方法を提供する。特定の局面において、方法は、本明細書に記載の化合物を含む組成物を哺乳動物に投与する段階を含んでもよい。本明細書に記載の化合物を含む組成物は、哺乳動物において神経形成を刺激するためおよび/またはニューロン変性を阻害するために有効な量で投与されてもよい。
式中、
R1は、水素、アルキル、分岐アルキル、アリール、アラルキル、ベンジル、ナフチル、炭素原子1〜12個のシクロアルキル、または複素環であり、R1が水素ではない場合それはH、OH、アルキル、アルコキシ、ハロゲン、-CF3、-R2、-OR2、-SR2、-N(R2)2、-CN、-NO2、-NC(O)R2、-C(O)R2、-C(O)N(R2)2、-S(O)2R2、-S(O)2NR2、-S(O)R2、-C(O)R2、C(O)OR2、または-C(O)N(R2)2で置換されていてもよく、式中、各R2は独立して、H、アルキル、アルケニル、アルキニル、アリール、複素環、保護基、またはプロドラッグ部分であり;
Lは、[CH2]2-6、-CH2-(C=O)-CH2-、
であり;
Xは、S、SO2、O、またはNHであり;
Yは、
であり;
Zは、それぞれH、OH、アルキル、アルコキシ、ハロゲン、または-CF3で置換されていてもよい
であり;
Tは、O、S、またはNR1であり;
nは2または3であり;
式中、各R1は独立しており、かつ互いに同じであってもよく、または好ましくは異なっていてもよい。
および薬学的に許容される担体を含み、
式中、
R1は、水素、アルキル、分岐アルキル、アリール、アラルキル、ベンジル、ナフチル、炭素原子1〜12個のシクロアルキル、または複素環であり、R1が水素ではない場合それはH、OH、アルキル、アルコキシ、ハロゲン、-CF3、-R2、-OR2、-SR2、-N(R2)2、-CN、-NO2、-NC(O)R2、-C(O)R2、-C(O)N(R2)2、-S(O)2R2、-S(O)2NR2、-S(O)R2、-C(O)R2、C(O)OR2、または-C(O)N(R2)2で置換されていてもよく、式中、各R2は独立して、H、アルキル、アルケニル、アルキニル、アリール、複素環、保護基、またはプロドラッグ部分であり;
Lは、[CH2]2-6、-CH2-(C=O)-CH2-、
であり;
Xは、S、SO2、O、またはNHであり;
Yは、
であり;
Zは、それぞれH、OH、アルキル、アルコキシ、ハロゲン、または-CF3で置換されていてもよい
であり;
Tは、O、S、またはNR1であり;
nは2または3であり;
式中、各R1は独立しており、かつ互いに同じであってもよく、または好ましくは異なっていてもよく、
任意で、薬学的組成物は、神経変性疾患、精神障害、および加齢からなる群より選択される状態を処置するために、それを必要とする患者に投与される。
、およびその薬学的に許容される塩、水和物、または溶媒和物からなる群より選択される化合物、ならびに薬学的担体を含む。
実施例1:化合物の同定
ヒトニューロン前駆細胞を用いてインビトロ神経形成試験を行った。背景として、ヒトニューロン前駆細胞は、培地において培養することができ、かつ成熟した機能的ニューロンの産生能を有し得る。培養培地における神経形成因子は、ニューロンに分化する前駆細胞数を促進することができる。実際に、これは、化学物質の神経形成特性を調べるための広く受け入れられているインビトロモデルである。
有効な化合物をインビトロニューロン変性試験に供した。ニューロン保護剤を発見するために適用されるこの試験は、アポトーシスおよび壊死を薬物が阻害する能力を必要とした。
1. H-結合ドナー(OHとNHの合計として表記される)が5個より多く存在する。
2. 分子量が500を超えている。
3. Logpが5を超えている(またはMLogPが4.15を超えている)。
4. H-結合アクセプター(NとOの合計として表記される)が10個より多く存在する。
Claims (5)
- 哺乳動物がヒトである、請求項3記載の薬学的組成物。
- ヒトが、神経変性疾患、脳損傷、神経損傷、精神障害、および加齢からなる群より選択される状態を患っている患者である、請求項4記載の薬学的組成物。
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