JP6695323B2 - ピリド[3,4−d]ピリミジン−2,4(1H,3H)−ジオン誘導体 - Google Patents
ピリド[3,4−d]ピリミジン−2,4(1H,3H)−ジオン誘導体 Download PDFInfo
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- JP6695323B2 JP6695323B2 JP2017508037A JP2017508037A JP6695323B2 JP 6695323 B2 JP6695323 B2 JP 6695323B2 JP 2017508037 A JP2017508037 A JP 2017508037A JP 2017508037 A JP2017508037 A JP 2017508037A JP 6695323 B2 JP6695323 B2 JP 6695323B2
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- trpc5
- pyrimidine
- methyl
- mmol
- compound
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- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000004672 propanoic acids Chemical class 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
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- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
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- 239000013557 residual solvent Substances 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 208000019116 sleep disease Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
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- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
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- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 230000008961 swelling Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本願は、TRPC5調節因子としての新規ピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン誘導体およびその使用、前記誘導体を含有する医薬組成物ならびにTRPC5受容体介在性障害または症状の処置のための薬剤としてのそれらの使用方法に関する。
様々なイオンチャネルタンパク質は、細胞膜を透過するイオン流束を媒介するために存在する。イオンチャネルタンパク質の適切な発現および機能は、細胞機能、細胞内情報伝達などの維持に不可欠である。多数の疾患は、膜電位の制御不全または異常なカルシウム輸送に起因する。細胞での膜電位およびイオン流束を調節することにおいてイオンチャネルが最も重要であることを考慮に入れると、特定のイオンチャネルを促進または阻害できる薬物の同定は、研究手段および可能性のある治療薬として非常に興味深い。
本発明は、式(I):
R1は、1〜3つのC3-C10シクロアルキルで置換されていてもよいC2-C10ヒドロキシアルキルであり;
R2は、H、C1-C6アルキル、C2-C6アルケニル、C2-C6アルキニル、C3-C10シクロアルキル、C1-C10ヒドロキシアルキルまたはC1-C6アルコキシであり;
R3は、C1-C6アルキル、C2-C6アルケニル、C2-C6アルキニル、C1-C6アシル、C3-C10シクロアルキル、C1-C6アルコキシ、C4-C10シクロアルキルオキシ、ハロ、C1-C6ハロアルキル、C1-C6ハロアルコキシ、ヒドロキシル、C1-C10ヒドロキシアルキル、アルキルチオ、チオニル、スルホニル、スルホンアミジル、C6-C12アリール、5〜14員ヘテロアリール、C6-C12アリール-C1-C6アルキル、5〜14員ヘテロアリール-C1-C6アルキル、C6-C12アリールオキシ、-O-C6-C12アリール-C1-C6アルキル、-O-C1-C6アルキル-C6-C12アリール、-C6-C12アリール-C1-C6アルキル-O、5〜14員ヘテロアリールオキシ、3〜18員ヘテロシクロアルキル、アミノ、C1-C6アルキルアミノ、C2-C12ジアルキルアミノ、-C(O)NH-、-C(O)N-C1-C6アルキル-、-NHC(O)-、-N-C1-C6アルキルC(O)-、ウレア、スルホニルウレア、ニトロまたはシアノであり、これらは、所望により1〜5つのR5で置換されていてもよい;
R4は、H、C1-C6アルキル、C2-C6アルケニル、C2-C6アルキニル、C1-C6アシル、C3-C10シクロアルキル、C1-C6アルコキシ、C4-C10シクロアルキルオキシ、ハロ、C1-C6ハロアルキル、C1-C6ハロアルコキシ、ヒドロキシル、C1-C10ヒドロキシアルキル、アルキルチオ、チオニル、スルホニル、スルホンアミジル、C6-C12アリール、5〜14員ヘテロアリール、C6-C12アリール-C1-C6アルキル、5〜14員ヘテロアリール-C1-C6アルキル、C6-C12アリールオキシ、-O-C6-C12アリール-C1-C6アルキル、-O-C1-C6アルキル-C6-C12アリール、-C6-C12アリール-C1-C6アルキル-O、5〜14員ヘテロアリールオキシ、3〜18員ヘテロシクロアルキル、アミノ、C1-C6アルキルアミノ、C2-C12ジアルキルアミノ、-C(O)NH-、-C(O)N-C1-C6アルキル-、-NHC(O)-、-N-C1-C6アルキルC(O)-、ウレア、スルホニルウレア、ニトロまたはシアノであり、これらは所望により1〜5つのR5で置換されていてもよい;および
各R5は、独立して、C1-C6アルキル、ハロ、C1-C6ハロアルキル、C1-C6ハロアルコキシ、ヒドロキシル、C1-C6アルコキシ、C6-C12アリール、5〜14員ヘテロアリール、C6-C12アリールオキシ、-O-C6-C12アリール-C1-C6アルキル、-O-C1-C6アルキル-C6-C12アリール、-C6-C12アリール-C1-C6アルキル-O、5〜14員ヘテロアリールオキシ、-C(O)O-C1-C6アルキル、C(O)-C1-C6アルキル、-C(O)OH、ニトロまたはシアノである]
の化合物またはその医薬的に許容される塩を提供する。
本明細書の様々な箇所において、本願に記載の化合物の置換基は、グループまたは範囲をもって開示される。具体的には、本発明は、そうしたグループおよび範囲の構成要素の各々およびすべてのサブコンビネーションを含むことを意図する。例えば、用語「C1-6アルキル」は、具体的にメチル、エチル、C3アルキル、C4アルキル、C5アルキル、およびC6アルキルをそれぞれ開示することを意図する。
であってもよい。
のような構造として表されてもよい。
ある特定の実施態様において、本発明は、インビトロまたはインビボにおいてTRPC5チャネルの機能を拮抗するための方法および組成物を提供する。典型的な機能としては、TRPC5-介在性電流が挙げられるが、これに限定されない。ある特定の実施態様において、本発明は、本願に記載の化合物を投与することにより疾患、障害または病態を処置する方法を提供する。他の実施態様において、本明細書に記載の化合物は、タンパク質の発現レベルおよび/または活性を選択的に阻害する。言い換えると、ある特定の実施態様において、本明細書に記載の化合物は、1以上の他のイオンチャネルの活性と比較してTRPC5タンパク質の活性を選択的に阻害する。
ある特定の実施態様において、本願に記載の化合物は、不安および恐怖に関連した障害を防止または処置するために用いられ得る(例えば、Riccio et al. (2009) Cell 137:761-72参照)。そうした障害の例としては、外傷後ストレス障害、パニック障害、広場恐怖症、社会恐怖症、全般性不安障害、パニック障害、社会不安障害、強迫性障害、および分離不安が挙げられる。
式Iの化合物は、パーキンソン病、癲癇、記憶障害、卒中、発作および気分障害の処置にも有用である。気分障害としては、うつ病(例えば、大うつ、精神的うつ病、気分変調症および産後うつ病)および双極性障害(例えば、双極性I、双極性II、および気分循環症)が挙げられる。記憶障害は、任意の記憶欠如に関連する病態であり、アルツハイマー病、健忘症、失語症、アテローム性動脈硬化症、脳傷害または障害、脳腫瘍、慢性疲労症候群、クロイツフェルト・ヤコブ病、解離性健忘症、うつ病、徘徊性健忘症、ハンチントン病、学習障害、睡眠障害、多重人格障害、疼痛、外傷後ストレス障害、統合失調症、スポーツでの怪我、卒中、およびウェルニッケ・コルサコフ症候群により生じ得る。
ある特定の実施態様において、式Iの化合物は、疼痛を処置または軽減するために用いられる。式(I)で示される化合物を用いて処置され得る疼痛の典型的な分類としては、侵害受容性疼痛、炎症性疼痛および神経障害性疼痛が挙げられるが、これらに限定されない。該疼痛は、慢性または急性であり得る。
神経変性疾患および障害としては、アルツハイマー病(AD)、パーキンソン病、ハンチントン病、筋萎縮性側索硬化症(ALS)および心的外傷または他の加齢を含む損傷によって生じる他の脳障害が挙げられるが、これらに限定されない。
様々な起源の興奮毒性は、発作を引き起こす。通常の過剰なニューロン発火は、発作活動を生じさせる。関連する神経集団の過剰興奮性を減少させる化合物は、発作活動を減少させることについて大きな可能性を有する。
TRPC5は、腎臓の糸球体足細胞(podocyte)内でも発現している。糸球体足細胞においてTRPC5およびTRPC6によるアクチン動態および細胞の拮抗的制御があると提示されている(Tian et al., (2010) Science Signaling)。したがって、TRPC5を阻害することは、傷害に対する糸球体足細胞の反応に影響を与え得る。
本発明は、インビトロおよびインビボにおいて使用するための式Iの化合物を提供する。本発明は、TRPC5活性を阻害する式(I)の化合物を含む組成物および医薬組成物も提供する。ある特定の実施態様において、式(I)の化合物は、選択的である。言い換えると、ある特定の実施態様において、式(I)の化合物は、TRPC5活性を他のイオンチャネルの活性に比べて優先的に阻害する。ある特定の実施態様において、式(I)の化合物は、TRPC5活性を、TRPV1、TRPV2、TRPV3、TRPV4、TRPC3、TRPC6、TRPC7、TRPA1、および/またはTRPM8活性よりも優先的に阻害する。例えば、ある特定の実施態様においては、式(I)の化合物は、TRPC5の活性を阻害し、また1以上のTRPC4、TRPV1、TRPV2、TRPV3、TRPV4、TRPC3、TRPC6、TRPC7、TRPA1、およびTRPM8の活性を阻害する。
本発明の化合物を投与するための適切な製品は、当業者には明らかであろうが、例えば、錠剤、ピル、カプセル剤、坐剤、トローチ剤、トローチ、液剤、シロップ、エリキシル剤、サシュ、注射剤、吸入剤、散剤などを包含する。医薬的に活性な化合物の含量は、全体として組成物中の0.1〜95 重量%、好ましくは5.0〜90重量%の範囲内であるべきである。
1日あたり適用できる本発明の化合物の用量範囲は、通常、1〜1000 mg、好ましくは5〜800 mg、より好ましくは25〜500 mgである。各投薬単位は、好都合には1〜1000 mg、好ましくは25〜500 mgを含有してもよい。
TRPC5機能を拮抗する式Iの化合物は、任意の前述した傷害、疾患、障害または病態の予防および処置において有用であり得る。式Iの化合物の活性のインビトロアッセイに加えて、その有効性は、1以上の動物モデルで容易に試験され得る。例として、多くのよく知られた動物モデルが存在する。1以上の適切な動物モデル(例えば、特定の適応を考慮して適切なモデル)を選択できる。
このアッセイは、TRPC5チャネルを誘導発現する細胞において、細胞内Ca2+濃度([Ca2+]i)の上昇後のチャネル活性化を検出することによる。Ca2+の上昇は、蛍光Ca2+インディケーターを使用して定量されるが、この蛍光Ca2+インディケーターは細胞内にロードされ、その後[Ca2+]i Ca2+流入に続くTRPC5チャネルの活性化を示す。[Ca2+]iの上昇を阻害する化合物を、更なる調査のためのヒット化合物と考えた。
陽性コントロールの条件は、TRPC5および他のチャネルの無差別ブロッカーである2-APBをプレートの列23および24に添加して、200μMの終濃度とすることからなる。これらのコントロールはスクリーニングウィンドウとして規定して、「ヒット」とは、少なくとも40%まで蛍光応答を阻害するそれらの化合物として定義した。IC50 値を、「ヒット」として定義した化合物について決定した。Fluo4 細胞を基にした蛍光アッセイを使用して、存在する薬剤濃度を変化させて、細胞内Ca2+濃度を決定した。試験した化合物の最終濃度は、20 μM、6.667 μM、2.222 μM、0.741 μM、0.247 μM、0.082 μMおよび0.027 μMであった。化合物を、全濃度にて3回試験した。標準ソフトウェアを使用して、IC50曲線を適合した。NF値を、IC50曲線が適合しなかった場合に割り当てた。
パッチクランプ実験は、上記の細胞株におけるTRPC5チャネルを通る電流の測定を可能にする。通常の全細胞パッチクランプの記録においては、ガラス電極を単一細胞に接触させ、高抵抗(ギガオーム)シールを細胞膜に設置する。その後、膜を断裂して、全細胞配置を得て、細胞膜電位のコントロールおよび電極に接続した増幅器を用いる膜を通る電流の測定が可能となり、ピペット溶液による細胞質の置換をもたらす。潅流システムにより、電流のブロッカーおよびアクティベーターの添加を含めた細胞外溶液のコントロールが可能となる。電流を、ピペット(細胞内)溶液中に1.4 μMの遊離Ca2+および細胞外溶液中に80 μMのLaCl3を含有させることにより活性化できる。
一般的な手順
すべての試薬を、市販業者から購入し、別段の記載がない限り、さらに精製することなく用いた。反応を、薄層シリカゲルプレート(TLC)により追跡し、UVライト(254 nmまたは365 nm)を用いて、および/またはDNP溶液(12 g、2,4-ジニトロフェニルヒドラジン、60 mL濃H2SO4、80 ml H2O、200 mLエタノール)で染色して可視化し、その後加熱するか、またはLCMSにより追跡した。使用した分取TLCプレートは、Analtech Uniplate Silica Gel GFプレートまたはShanghia SANPONT PLC プレート SGF254 20 x 20 cmサイズおよび2000 um 厚みであった。
4-メトキシ-4-オキソブタン酸(9.7 g, 73.5 mmol)/トルエン(368 mL)の溶液に、ジフェニルホスホリルアジド(20.2 g, 73.5 mmol)、次いでTEA(12.4 g, 122.7 mmol)を加えた。この反応溶液を、RTで30分間攪拌して、5-アミノ-2-クロロイソニコチン酸(8.47 g, 49 mmol)を加えた。この反応溶液を、6時間還流加熱して、RTに冷却して、EA(300 mL)で希釈した。この混合物を、食塩水(300 mL)で洗い、有機層以外の沈殿した固体を濾過した。水層を分けて、2N HCl水溶液を加えて、PH5に酸性化して、沈殿物を形成させた。固体を、濾過して、有機層の固体と合わせた。合わせた固体を、乾燥させて、2-クロロ-5-(3-(3-メトキシ-3-オキソプロピル)ウレイド)イソニコチン酸(26 g, >100% 収率)を褐色半固体として得た。LCMS:MH+ 302 MH+ および TR = 2.752分。さらなる精製をせずに使用した。
2-クロロ-5-(3-(3-メトキシ-3-オキソプロピル)ウレイド)イソニコチン酸(33.8 g, 112 mmol)/アセトン(386 mL)の溶液に、K2CO3(46.4 g, 336 mmol)、次いでCH3I(95.4 g, 672 mmol)を加えた。反応溶液を、密封管内において40℃で24時間加熱して、RTに冷却して、濃縮して、EA(200 mL)および水(100 mL)で希釈した。有機層を、食塩水(100 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、PE/EA(10:1〜2:1)で溶出されるクロマトグラフィーにより精製して、メチル 3-(6-クロロ-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロパノエート(1.6 g, 11% 収率)を黄色固体として得た。LCMS:MH+ 298 および TR= 2.857分。
5-(4-クロロベンジル)-6-(4-クロロフェニル)-3-(3-ヒドロキシプロピル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
工程1 3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(4-クロロフェニル)-5-((4-クロロフェニル)(ヒドロキシ)メチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
6-(4-クロロフェニル)-3-(3-ヒドロキシプロピル)-5-イソペンチル-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
工程1 3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-5-(1-ヒドロキシ-3-メチルブチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(参照、化合物49, 工程3, 1.149 g, 3 mmol)/THF(30 mL) の溶液に、-78℃で、LDA(THF中で2M, 7.5 mL, 15 mmol)を滴加した。この反応溶液を、-78℃で30分間攪拌して、次いで3-メチルブタナール(516 mg, 6 mmol)/THF(5mL)を、滴加した。この反応溶液を、-78℃で20分間攪拌して、NH4Cl水溶液を用いてクエンチして(5 mL)、EA(15 mL)および水(5 mL)で希釈した。有機層を、食塩水(20 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、PE/EA(2:1)で溶出されるクロマトグラフィーにより精製して、3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-5-(1-ヒドロキシ-3-メチルブチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(464 mg, 30% 収率)を、白色の固形物として得た。LCMS:MH+ 470 および TR= 2.198分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-5-(1-ヒドロキシ-3-メチルブチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(100 mg, 0.212 mmol)、4-クロロフェニルボロン酸(66 mg, 0.424 mmol)、NaHCO3(53 mg, 1.06 mmol)、2M K3PO4水溶液(0.53 mL, 1.06 mmol)/ジオキサン(1 mL)および水(0.2 mL)の溶液に、Pd(dppf)Cl2(5 mg, 0.0068 mmol)を加えた。反応溶液を、窒素で脱気して(3x)、120℃(MW)で1.5時間加熱して、RTに冷却して、EA(10 mL)および水(2 mL)で希釈した。反応溶液を濾過して、濾液を、濃縮して、残留物を得て、これを、PE/EA(2:1)で溶出されるPrepTLCにより精製して、3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(4-クロロフェニル)-5-(1-ヒドロキシ-3-メチルブチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(30 mg, 26% 収率)を、無色油状物として得た。LCMS:MH+ 546 および TR= 2.602分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(4-クロロフェニル)-5-(1-ヒドロキシ-3-メチルブチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(30 mg, 0.055 mmol)/HCOOH(1 mL)の溶液に、Zn粉(35.6 mg, 0.55 mmol)を加えた。反応溶液を、50℃で1時間加熱して、RTに冷却して、EA(5 mL)および水(1 mL)で希釈した。有機層を、食塩水(1 mL)で洗い、Na2SO4上で乾燥し、濃縮して、3-(6-(4-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート;LCMS:MH+ 444 および TR=1.765分 ならびに 3-(6-(4-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2,7,8-テトラヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート;LCMS:MH+ 446 および TR= 1.997 分(22 mg, 73% 収率)の混合物を、油状物として得た。さらなる精製をせずに使用した。
3-(6-(4-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメートおよび3-(6-(4-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2,7,8-テトラヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(20 mg, 0.0495 mmol)/DCM(1 mL)の溶液に、MnO2(43 mg, 0.495 mmol)を加えた。この反応溶液を、RTで3時間攪拌して、次いでDCM(5 mL)および水(1 mL)で希釈した。有機層を、食塩水(1 mL)で洗い、Na2SO4上で乾燥させて、濃縮して、3-(6-(4-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(13 mg, 65% 収率)を油状物として得た。LCMS:MH+ 444 および TR= 1.994分。
5-アミノ-2-クロロイソニコチン酸(5 g, 0.029 mol)/DMF(40 mL)の溶液に、EDCI(8.34 g, 0.0435 mol)およびHOBT(5.87 g, 0.0435 mol)を加えた。この反応溶液を、RTで30分間攪拌して、3-(tert-ブチルジメチルシリルオキシ)プロパン-1-アミン(5.5 g, 0.029 mol)を加えた。この反応溶液を、RTで5h攪拌して、EA(50 mL)および水(20 mL)に注ぎ入れた。有機層を、食塩水(50 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、PE/EA(2:1)で溶出されるクロマトグラフィーにより精製して、5-アミノ-N-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-2-クロロイソニコチンアミド(4.3 g, 43% 収率)を、白色の固形物として得た。LCMS:MH+ 344 および TR= 1.877分。
5-アミノ-N-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-2-クロロイソニコチンアミド(4.3 g, 0.0125 mol)/THF(40 mL)の溶液に、CDI(5.46 g, 0.03375 mmol)およびDBU(5.13 g, 0.03375 mmol)を加えた。この反応溶液を、RTで3時間攪拌して、次いでEA(50 mL)および水(10 mL)で希釈した。有機層を、食塩水(8 mL)で洗い、Na2SO4上で乾燥して、濃縮して、残留物とし、これを、クロマトグラフィーにより精製して、PE/EA(2:1)で溶出して、tert-ブチル 3-((8-ブロモ-1,3-ジメチル-3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(3.3 g, 72% 収率)を、白色の固形物として得た。LCMS:MH+ 370 および TR= 1.939分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(383 mg, 1 mmol)/THF(4 mL)の溶液に、-78℃で、LDA(1.8N/THF, 2.7 mL,4.86 mmol)を滴加した。この反応溶液を、-78℃で30分間攪拌して、次いで4-クロロベンズアルデヒド(280 mg, 2 mmol)/THF(1 mL)を滴加した。20分間攪拌した後に、この反応溶液を、NH4Cl水溶液を用いてクエンチして(2 mL)、次いでEA(5 mL)および水(2 mL)で希釈した。有機層を、食塩水(5mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、PE/EA(2:1)で溶出されるクロマトグラフィーにより精製して、3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-5-((4-クロロフェニル)(ヒドロキシ)メチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(155 mg, 30% 収率)を、白色の固形物として得た。LCMS:(M+-OH-H)506 および TR= 2.357分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-5-((4-クロロフェニル)(ヒドロキシ)メチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(100 mg, 0.19 mmol)、2-イソプロピルフェニルボロン酸(62.52 mg, 0.38 mmol)、NaHCO3(48 mg, 0.57 mmol)、2M K3PO4水溶液(0.47 mL, 0.94 mmol)/ジオキサン(1 mL)および水(0.2 mL)の溶液に、Pd(dppf)Cl2(5 mg, 0.0068 mmol)を加えた。反応溶液を、窒素で脱気して(3x)、120℃(MW)で1.5時間加熱して、RTに冷却して、EA(10 mL)および水(2 mL)で希釈して、濾過した。濾液を濃縮して、残留物を得て、これをPE/EA(2:1)で溶出されるPrepTLCにより精製して、3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-5-((4-クロロフェニル)(ヒドロキシ)メチル)-6-(2-イソプロピルフェニル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(15 mg, 12.9% 収率)を、無色油状物として得た。LCMS:MH+ 608 および TR= 2.668分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-5-((4-クロロフェニル)(ヒドロキシ)メチル)-6-(2-イソプロピルフェニル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(15 mg, 0.0247 mmol)/HCOOH(1 mL)の溶液に、Zn粉(8 mg, 0.123 mmol)を加えた。反応溶液を、50℃で1時間加熱して、RTに冷却して、EA(5 mL)および水(1 mL)で希釈した。有機層を、食塩水(1 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、PE/EA(2:1)で溶出されるPrepTLCにより精製して、3-(5-(4-クロロベンジル)-6-(2-イソプロピルフェニル)-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(7 mg, 56% 収率)を、無色油状物として得た。LCMS:MH+ 506 および TR= 2.225分。
3-(5-(4-クロロベンジル)-6-(2-イソプロピルフェニル)-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(7 mg, 0.0138 mmol)/THF(0.5 mL)および水(0.5 mL)の溶液に、LiOH・H2O(1.2 mg, 0.0277 mmol)を加えた。この反応溶液を、RTで30分間攪拌して、次いでEA(5 mL)で希釈した。有機層を、食塩水(10 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、PE/EA(1:2)で溶出されるPrepTLCにより精製して、5-(4-クロロベンジル)-3-(3-ヒドロキシプロピル)-6-(2-イソプロピルフェニル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(2.4 mg, 36.4% 収率)を、白色の固形物として得た。1H NMR(CDCl3)δ: 8.79(s, 1H), 7.38(d, J = 3.8 Hz, 2H), 7.20-7.12(m, 1H), 7.10(t, J = 8.4 Hz, 2H), 6.97(d, J = 7.5 Hz, 1H), 6.71(d, J = 8.4 Hz, 2H), 5.34(s, 1H), 4.79(d, J = 14.9 Hz, 1H), 4.19(t, J = 6.1 Hz, 2H), 3.76(s, 3H), 3.48(d, J = 6.1 Hz, 2H), 2.77(s, 1H), 2.01(d, J = 5.9 Hz, 1H), 1.92-1.80(m, 2H), 1.10(d, J = 6.8 Hz, 3H), 1.02(d, J = 6.9 Hz, 3H). LCMS:MH+ 478 および TR= 4.088分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-5-(1-ヒドロキシ-3-メチルブチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(参照、化合物48, 工程1, 130 mg, 0.277 mmol)、2-イソプロピルフェニルボロン酸(90.8 mg, 0.554mmol)、2M K3PO4水溶液(0.68 mL,1.35 mmol)/ジオキサン(1 mL)および水(0.2 mL)の溶液に、Pd(dppf)Cl2(8 mg, 0.01 mmol)を加えた。反応溶液を、窒素で脱気して(3x)、120℃(MW)で1.5時間加熱して、RTに冷却して、EA(10 mL)および水(2 mL)で希釈して、濾過した。濾液を濃縮して、残留物とし、これをPrepTLC, PE/EA(2:1)により精製して、3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-5-(1-ヒドロキシ-3-メチルブチル)-6-(2-イソプロピルフェニル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(22 mg, 14.3% 収率)を、無色油状物として得た。LCMS:MH+ 554 および TR= 2.415分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-5-(1-ヒドロキシ-3-メチルブチル)-6-(2-イソプロピルフェニル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(20 mg, 0.036 mmol)/HCOOH(1 mL)の溶液に、Zn粉(23.4 mg, 0.36 mmol)を加えた。反応溶液を、50℃で1時間加熱して、RTに冷却して、次いでEA(5 mL)および水(1 mL)で希釈した。有機層を、食塩水(1 mL)で洗い、Na2SO4上で乾燥し、濃縮して、3-(5-イソペンチル-6-(2-イソプロピルフェニル)-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)イル)プロピルホルメート;LCMS:MH+ 452 および TR= 1.745分 ならびに 3-(5-イソペンチル-6-(2-イソプロピルフェニル)-1-メチル-2,4-ジオキソ-1,2,7,8-テトラヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート;LCMS:MH+ 454 および TR= 1.923 分(15 mg, 75% 収率)の混合物を、油状物として得た。さらなる精製をせずに使用した。
3-(5-イソペンチル-6-(2-イソプロピルフェニル)-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメートおよび3-(5-イソペンチル-6-(2-イソプロピルフェニル)-1-メチル-2,4-ジオキソ-1,2,7,8-テトラヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(15 mg, 0.033 mmol)/DCM(1 mL)の溶液に、MnO2(28.9 mg, 0.33 mmol)を加えた。この反応溶液を、RTで3時間攪拌して、次いでDCM(5 mL)および水(1 mL)で希釈した。有機層を、食塩水(1 mL)で洗い、Na2SO4上で乾燥し、濃縮して、3-(5-イソペンチル-6-(2-イソプロピルフェニル)-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(11 mg, 73% 収率)を固体として得た。LCMS:MH+ 452 および TR= 1.921分。さらなる精製をせずに使用した。
3-(5-イソペンチル-6-(2-イソプロピルフェニル)-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(10 mg, 0.022 mmol/THF(0.5 mL)および水(0.5 mL)の溶液に、LiOH・H2Oを加えた(1.8 mg, 0.044 mmol)。この反応溶液を、RTで30分間攪拌して、次いでEA(5 mL)で希釈した。有機層を、食塩水(5 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、Prep HPLCにより精製して、3-(3-ヒドロキシプロピル)-5-イソペンチル-6-(2-イソプロピルフェニル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(2.2 mg, 23.6% 収率)を、白色の固形物として得た。1H NMR(CDCl3)δ: 8.66(s, 1H), 7.41(d, J = 3.8 Hz, 2H), 7.26-7.23(m, 1H), 7.11(d, J = 7.5 Hz, 1H), 4.28(t, J = 6.1 Hz, 2H), 3.72(s, 3H), 3.65-3.54(m, 2H), 3.35(td, J = 11.8, 4.5 Hz, 1H), 3.14(t, J = 6.6 Hz, 1H), 2.69(d, J = 11.9, 4.4 Hz, 1H), 2.53-2.40(m, 1H), 2.04-1.91(m, 2H), 1.45(d, J = 12.9, 6.4 Hz, 1H), 1.38-1.32(m, 1H), 1.19(d, J = 6.9 Hz, 3H), 1.14(dd, J = 7.1, 4.8 Hz, 1H), 1.10(d, J = 6.8 Hz, 3H), 0.72(d, J = 6.6 Hz, 3H), 0.65(d, J = 6.6 Hz, 3H). LCMS:MH+ 424 および TR= 3.102 分。
5-(4-クロロベンジル)-6-(3-クロロフェノキシ)-3-(3-ヒドロキシプロピル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
ジオキサン(6 mL)中の3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(化合物49, 工程3を参照, 383 mg, 1 mmol)、CuI(24.7 mg, 0.13 mmol)、Cs2CO3(650 mg, 2 mmol)、2-(ジメチルアミノ)酢酸(51.5 mg, 0.5 mmol)の混合物に、3-クロロフェノール(192 mg, 1.5 mmol)を加えた。反応混合物を、140℃(MW)で2.5時間加熱して、RTに冷却して、Celiteパッドを通して濾過した。濾液を、EA(20 mL)および水(20 mL)で希釈した。有機層を、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、PE/EA(2:1)で溶出されるクロマトグラフィーにより精製して、3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(3-クロロフェノキシ)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(300 mg, 63% 収率)を固体として得た。LCMS:MH+ 476 および TR= 2.377分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(3-クロロフェノキシ)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(150 mg, 0.315 mmol)/THF(4 mL)の溶液に、-78℃で、LDA(THF中で2.0 M, 0.79 mL,1.58 mmol)を滴加した。この反応溶液を、-78℃で1時間攪拌して、次いで4-クロロベンズアルデヒド(88 mg, 0.625 mmol)/THF(1 mL)の溶液を加えた。この反応溶液を、-78℃で30分間攪拌して、NH4Cl水溶液を用いてクエンチして(3 mL)、次いでEA(20 mL)および水(20 mL)で希釈した。有機層を、Na2SO4上で乾燥し、濃縮して、残留物を得て、これをPE/EA(2:1)によるクロマトグラフィーにより精製して、3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(3-クロロフェノキシ)-5-((4-クロロフェニル)(ヒドロキシ)メチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(56 mg, 29% 収率)を固体として得た。LCMS:(M+-OH)598 および TR= 2.221分。
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(3-クロロフェノキシ)-5-((4-クロロフェニル)(ヒドロキシ)メチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(56 mg, 0.091 mmol)/HCOOH(3 mL)の溶液に、Zn粉(59 mg, 0.91 mmol)を加えた。反応を、50℃で45分間加熱して、RTに冷却して、濾過した。濾液を濃縮して、3-(5-(4-クロロベンジル)-6-(3-クロロフェノキシ)-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(20 mg, 41.2% 収率)を、油状物として得た。LCMS:MH+ 514 および TR= 1.901分。 さらなる精製をせずに使用した。
3-(5-(4-クロロベンジル)-6-(3-クロロフェノキシ)-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(20 mg, 0.0389 mmol)/THF(2 mL)および水(2 mL)の溶液に、LiOH・H2O(3.2 mg, 0.078 mmol)を加えた。この反応溶液を、RTで15分間撹拌して、EA(20 mL)および水(20 mL)で希釈した。有機層を、Na2SO4上で乾燥し、濃縮して、残留物を得て、これをPrep HPLCにより精製して、5-(4-クロロベンジル)-6-(3-クロロフェノキシ)-3-(3-ヒドロキシプロピル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(5 mg, 26% 収率)を、白色の固形物として得た。1H NMR(CDCl3)δ: 8.20(s, 1H), 7.74(dd, J = 11.1, 9.8, 5.7 Hz, 2H), 7.32(t, J = 8.1 Hz, 1H), 7.23-7.16(m, 3H), 7.03(t, J = 2.1 Hz, 1H), 6.90(dd, J = 8.2, 1.5 Hz, 1H), 4.82(s, 2H), 4.24(t, J = 6.2 Hz, 2H), 3.60(d, J = 13.0 Hz, 3H), 3.56(d, J = 5.6 Hz, 2H), 2.87(s, 1H), 1.99-1.84(m, 2H). LCMS:MH+ 486 および TR= 3.024分。
6-(3-クロロフェニル)-3-(3-ヒドロキシプロピル)-5-イソペンチル-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
工程1.3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(3-クロロフェニル)-5-(1-ヒドロキシ-3-メチルブチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-(3-クロロフェニル)-5-(1-ヒドロキシ-3-メチルブチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(30 mg, 0.055 mmol)/HCOOH(1 mL)の溶液に、Zn粉(35.6 mg, 0.55 mmol)を加えた。反応溶液を、50℃で1時間加熱して、RTに冷却して、EA(5 mL)および水(1 mL)で希釈した。有機層を、食塩水(1 mL)で洗い、Na2SO4上で乾燥し、濃縮して、3-(6-(3-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート;LCMS MH+ 444 および TR= 1.738分 ならびに 3-(6-(3-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2,7,8-テトラヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート;LCMS:MH+ 446 および TR= 1.956 分(21 mg, 70% 収率)を固体として得た。さらなる精製をせずに使用した。
3-(6-(3-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメートおよび3-(6-(3-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2,7,8-テトラヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(21 mg, 0.047 mmol)/DCM(1 mL)の溶液に、MnO2(40.8 mg, 0.47 mmol)を加えた。この反応溶液を、RTで3時間攪拌して、次いでDCM(5 mL)および水(1 mL)で希釈した。有機層を、食塩水(1 mL)で洗い、Na2SO4上で乾燥して、濃縮し、3-(6-(4-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(14 mg, 66.7% 収率)を油状物として得た。LCMS:MH+ 444 および TR= 1.942分。さらなる精製をせずに使用した。
3-(6-(3-クロロフェニル)-5-イソペンチル-1-メチル-2,4-ジオキソ-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(14 mg, 0.0316 mmol)/THF(0.5 mL)およびH2O(0.5 mL)の溶液に、LiOH・H2O(2.46 mg, 0.058 mmol)を加えた。この反応溶液を、RTで30分間攪拌して、次いでEA(5 mL)で希釈した。有機層を、食塩水(5 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、Prep HPLCにより精製して、6-(3-クロロフェニル)-3-(3-ヒドロキシプロピル)-5-イソペンチル-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(7.1 mg, 54% 収率)を、白色の固形物として得た。1H NMR(CDCl3)δ: 8.65(s, 1H), 7.46-7.37(m, 3H), 7.31-7.27(m, 1H), 4.28(t, J = 6.1 Hz, 2H), 3.72(s, 3H), 3.66-3.53(m, 2H), 3.24 - 3.13(m, 2H), 3.07(s, 1H), 2.02-1.89(m, 2H), 1.54(td, J = 13.2, 6.6 Hz, 1H), 1.40-1.30(m, 2H), 0.78(d, J = 6.6 Hz, 6H). LCMS:MH+ 416 および TR= 3.048分。
5-ベンジル-3-(3-ヒドロキシプロピル)-1-メチル-6-(3-(トリフルオロメトキシ)フェニル)ピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
工程1 3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-5-(ヒドロキシ(フェニル)メチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン
3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-1-メチルピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(参照、化合物49, 工程3, 1.15 mg, 3.0 mmol)/THF(30 mL)の溶液に、-78℃で、LDA(THF中で2M, 6 mL, 12 mmol,)を滴加した。この反応溶液を、-78℃で30分攪拌して、次いでベンズアルデヒド(636 mg, 6.0 mmol)/THF(5mL)を滴加した。この反応溶液を、-78℃で20分間攪拌して、NH4Cl水溶液(5mL)でクエンチして、次いでEA(30 mL)および水(8 mL)で希釈した。有機層を、食塩水(20 mL)で洗い、Na2SO4上で乾燥して、濃縮して、残留物を得て、これをPE/EA(2:1)で溶出されるクロマトグラフィーにより精製して、3-(3-(tert-ブチルジメチルシリルオキシ)プロピル)-6-クロロ-5-(ヒドロキシ(フェニル)メチル)-1-メチルピリド[3,4-d]ピリミジン-2,4(1H, 3H)-ジオン(450 mg, 30.7% 収率)を、無色油状物として得た。LCMS:[M+-OH]472 および TR= 2.058分。
3-(5-ベンジル-1-メチル-2,4-ジオキソ-6-(3-(トリフルオロメトキシ)フェニル)-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメートおよび3-(5-ベンジル-1-メチル-2,4-ジオキソ-6-(3-(トリフルオロメトキシ)フェニル)-1,2,7,8-テトラヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(66 mg, 0.128 mmol)/DCM(3 mL)の溶液に、MnO2(223 mg, 2.57 mmol)を加えた。この反応溶液を、RTで3時間攪拌して、次いでDCM(5 mL)および水(1 mL)で希釈した。有機層を、食塩水(2 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これをPE/EA(2:1)で溶出されるPrepTLCにより精製して、3-(5-ベンジル-1-メチル-2,4-ジオキソ-6-(3-(トリフルオロメトキシ)フェニル)-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(50 mg, 75% 収率)を固体として得た。LCMS:MH+ 514 および TR= 1.864分。
3-(5-ベンジル-1-メチル-2,4-ジオキソ-6-(3-(トリフルオロメトキシ)フェニル)-1,2-ジヒドロピリド[3,4-d]ピリミジン-3(4H)-イル)プロピルホルメート(50 mg, 0.097 mmol)/THF(0.5 mL)および水(0.5 mL)の溶液に、LiOH・H2O(8.18 mg, 0.194 mmol)を加えた。この反応溶液を、RTで30分間攪拌して、次いでEA(5 mL)で希釈した。有機層を、食塩水(10 mL)で洗い、Na2SO4上で乾燥し、濃縮して、残留物を得て、これを、Prep HPLCにより精製して、5-ベンジル-3-(3-ヒドロキシプロピル)-1-メチル-6-(3-(トリフルオロメトキシ)フェニル)ピリド[3,4-d]ピリミジン-2,4(1H,3H)-ジオン(26.4 mg, 56% 収率)を、白色の固形物として得た。1H NMR(CDCl3)δ: 8.79(s, 1H), 7.45-7.37(m, 1H), 7.29(d, J = 7.7 Hz, 1H), 7.24(s, 2H), 7.22-7.11(m, 3H), 6.86(d, J = 7.1 Hz, 2H), 4.71(s, 2H), 4.18(t, J = 6.1 Hz, 2H), 3.73(d, J = 13.2 Hz, 3H), 3.42(t, J = 5.6 Hz, 2H), 1.88-1.76(m, 2H). LCMS:MH+ 486 および TR= 2.808分。
個々の公報または特許が具体的におよび個々に参照により組み込まれると示されているように、本明細書で言及したすべての公報および特許は、そのまま参照により本明細書に組み込まれる。
当業者は、本明細書に記載された発明の具体的な実施態様に対する多くの均等物を単なる通常の実験を用いて認識または確認できるであろう。そうした均等物を以下の請求の範囲に含包することを意図する。
Claims (13)
- R3が、フェノキシまたはフェニルであり、この各々は、所望により1〜5つの塩素または-OCF3で置換されていてもよい、請求項1記載の化合物。
- R4が、C6アルキルまたはベンジルであり、該ベンジル基は、所望により1〜5つの塩素で置換されていてもよい、請求項1〜3のいずれか1項記載の化合物。
- R4が、クロロベンジルまたはイソペンチルである、請求項1〜4のいずれか1項記載の化合物。
- 請求項8の化合物の医薬的に許容される塩。
- 医薬的に許容し得る賦形剤、希釈剤または担体を含む混合物中に、請求項1〜9のいずれか1項記載の少なくとも1つの化合物またはその医薬的に許容される塩を含む、医薬組成物。
- 医薬的に許容される賦形剤、希釈剤または担体との混合物中に、請求項1〜9のいずれか1項記載の少なくとも1つの化合物またはその医薬的に許容される塩を、抗うつ剤、抗不安薬、抗てんかん薬、抗炎症剤、抗片頭痛剤、鎮痛薬、麻酔薬および/または化学療法剤からなる群から選択される1以上の別の医薬的に活性な剤とを組み合わせて含む、医薬組成物。
- TRPC5介在性疾患の処置において使用するための、請求項1〜9のいずれか1項記載の少なくとも1つの化合物またはその医薬的に許容される塩を含有する医薬組成物。
- TRPC5介在性疾患が、精神神経障害、神経変性障害、腎障害および発作性疾患からなる群から選択される、請求項12記載の医薬組成物。
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