JP2021508739A - パントテン酸キナーゼの小分子モジュレーター - Google Patents
パントテン酸キナーゼの小分子モジュレーター Download PDFInfo
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- JP2021508739A JP2021508739A JP2020555731A JP2020555731A JP2021508739A JP 2021508739 A JP2021508739 A JP 2021508739A JP 2020555731 A JP2020555731 A JP 2020555731A JP 2020555731 A JP2020555731 A JP 2020555731A JP 2021508739 A JP2021508739 A JP 2021508739A
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- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 150000003398 sorbic acids Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 1
- 229910052815 sulfur oxide Inorganic materials 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 229910052714 tellurium Inorganic materials 0.000 description 1
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960001032 trihexyphenidyl Drugs 0.000 description 1
- 238000013024 troubleshooting Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000009492 vitamin B5 Nutrition 0.000 description 1
- 239000011675 vitamin B5 Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/20—Nitrogen atoms
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
本出願は、2017年12月27日に出願された米国特許仮出願第62/610,835号明細書の利益を主張するものであり、その全ての内容を参照により本明細書に援用する。
R3a、R3b及びR3cは、それぞれ独立に、水素、ハロゲン、C1〜C4アルコキシ及びC1〜C4アルキルから選択され、但し、R3a、R3b及びR3cの少なくとも1種はハロゲンであり;R4は、水素、ハロゲン、−CN、SO2NH2、SO2CH3、SO2CF3及びNO2から選択される)で表される構造を有する化合物又はその医薬的に許容される塩を開示する。
本明細書及び添付の特許請求の範囲において用いる単数形(a、an及びthe)は、文脈上明らかに他を指示していない限り、複数の指示対象を含む。したがって、例えば、「官能基(a functional group)」、「アルキル(an alkyl)」又は「残基(a residue)」に言及した場合、これは、2種以上のそのような官能基、アルキル又は残基の混合物を包含し、他も同様である。
一態様において、例えば、PKANや糖尿等のPanK活性が関連する障害を治療又は予防するのに有用な化合物を開示する。更なる態様において、開示された化合物はPanK活性を調節する。更なる他の態様において、開示された化合物はPanK活性を阻害する。更なる他の態様において、開示された化合物はPanK活性を活性化する。
一態様においては、式:
R3a、R3b及びR3cは、それぞれ独立に、水素、ハロゲン、C1〜C4アルコキシ及びC1〜C4アルキルから選択され、但し、R3a、R3b及びR3cの少なくとも1種はハロゲンであり;R4は、水素、ハロゲン、−CN、SO2NH2、SO2CH3、SO2CF3及びNO2から選択される)で表される構造を有する化合物又はその医薬的に許容される塩を開示する。
一態様において、Aは、O、CO、CH2、CF2、NH、N(CH3)及びCH(OH)から選択される。一態様において、Aは、O、CO、CH2、CF2、NH及びCH(OH)から選択される。一態様において、O、CO、CH2、CF2、N(CH3)及びCH(OH)から選択される。一態様において、Aは、O、CO、CH2、CF2及びCH(OH)から選択される。
一態様においては、Q2は:
一態様において、R3a、R3b及びR3cは、それぞれ独立に、水素、ハロゲン、C1〜C4アルコキシ及びC1〜C4アルキルから選択され、但し、R3a、R3b及びR3cの少なくとも1種はハロゲンである。更なる態様において、R3b及びR3cはそれぞれ水素である。更なる他の態様において、R3a及びR3cはそれぞれ水素である。更なる他の態様において、R3a及びR3bはそれぞれ水素である。
一態様において、R4は、水素、ハロゲン、−CN、SO2NH2、SO2CH3、SO2CF3及びNO2から選択される。更なる態様において、R4は水素である。
一態様において、化合物は、次に示す構造の1種以上を有するもの:
次に示す化合物例は予言的であり、本明細書において上に記載した合成方法、及び、必要に応じて、当業者に知られているであろう他の一般的な方法を用いて調製することができる。この予言的化合物はPanKアンタゴニストとして活性を示すことが期待され、そのような活性は、本明細書に記載する測定方法を用いて決定することができる。
本発明の化合物は、次に示すスキームに示す反応に加えて、文献から知られている、実験項に例示する、又は当業者に明らかな、他の標準的な操作を用いることにより調製することができる。明確にするために、本明細書に開示する定義の下に複数の置換が可能な場合も、単一の置換基を有する実施例を示す。
一態様においては、PanKの置換小分子モジュレーターを次に示すように調製することができる。
一態様においては、PanKの置換小分子モジュレーターを次に示すように調製することができる。
一態様においては、PanKの置換小分子モジュレーターを次に示すように調製することができる。
一態様において、PanKの置換小分子モジュレーターを次に示すように調製することができる。
一態様において、PanKの置換小分子モジュレーターを次に示すように調製することができる。
一態様においては、開示した化合物又はその医薬的に許容される塩及び医薬的に許容される担体を含む医薬組成物を開示する。
様々な態様において、本明細書に開示する化合物及び組成物は、パントテン酸キナーゼ活性が関連する、例えば、PKAN、老化及び糖尿を含む様々な障害の治療、予防、回復、制御(control)又はリスクの低下に有用である。したがって、一態様においては、対象のパントテン酸キナーゼ活性が関連する障害を治療する方法であって、対象に有効量の少なくとも1種の開示された化合物又はその医薬的に許容される塩を投与することを含む方法を開示する。
一態様においては、少なくとも1個の細胞のパントテン酸キナーゼ活性を調節する方法であって、少なくとも1個の細胞に、有効量の少なくとも1種の開示化合物又はその医薬的に許容される塩を接触させる工程を含む、方法を開示する。更なる態様において、調節は阻害である。
開示組成物又は医薬を使用する方法を提供する。一態様において、この使用方法は、障害の治療を対象とする。更なる態様において、開示化合物は、単独の剤として、又は1種以上の他の薬物と組み合わせて、該化合物又は該他の薬物が有用である上述の疾患、障害及び状態の治療、予防、制御、回復又はリスクの低下に使用することができ、この薬物の組合せは、いずれかの薬物を単独とするよりも安全又は有効である。他の薬物は、慣用されている経路及び量で、開示化合物と同時に又は順次投与することができる。開示化合物は、1種以上の他の薬物と同時に、この種の薬物及び開示化合物を含む単位剤形の医薬組成物中で使用することが好ましい。しかしながら、併用療法では、一部重複するスケジュールで投与することもできる。1種以上の活性成分及び開示化合物の組合せが、いずれかを単独の剤とするよりも有効となり得ることも想定されている。
一態様においては、本発明は、哺乳動物のPanK機能不全が関連する障害を治療するための医薬を製造するための方法であって、治療有効量の開示化合物又は開示方法の生成物を、医薬的に許容される担体又は希釈剤と組み合わせることを含む、方法に関する。
開示化合物及び組成物の使用も提供する。したがって、一態様において、本発明は、PanKのモジュレーターの使用に関する。
一態様において、開示化合物と:(a)PKANを治療することが知られている少なくとも1種の剤;(b)糖尿を治療することが知られている少なくとも1種の剤;(c)PKANを治療するための使用説明書;並びに(d)糖尿、メタボリック症候群及び/又は老化の副作用を治療するための使用説明書;のうちの1以上と、を含むキットを開示する。
様々な態様において、本明細書に開示する方法の対象は、脊椎動物、例えば、哺乳動物である。したがって、本明細書に開示する方法の対象は、ヒト、非ヒト霊長類、ウマ、ブタ、ウサギ、イヌ、ヒツジ、ヤギ、雌牛、ネコ、モルモット又は齧歯類動物とすることができる。この語は特定の年齢又は性別を意味するものではない。したがって、性別に関わらず、成体及び新生児の対象に加えて胎児の対象も包含することを意図している。患者は、疾患又は障害に罹患している対象を指す。「患者」という語は、ヒト及び動物の対象を含む。
本明細書に記載する剤及び医薬組成物の毒性及び治療効果は、LD50(集団の50%を致死させる量)及びED50(集団の50%の治療に有効な量)を決定するための、培養細胞又は実験動物のいずれかを用いる標準的な製薬手順により決定することができる。毒性及び治療効果の用量比は治療係数であり、LD50/ED50の比で表すことができる。治療係数の高いポリペプチド又は他の化合物が好ましい。
開示化合物及び組成物の投与経路も提供する。本発明の化合物及び組成物は、全身投与及び/又は局所投与を用いる直接療法により投与することができる。様々な態様において、投与経路は、患者の医療供給者又は臨床家により、例えば患者の診断に従い決定することができる。様々な態様において、個々の患者の療法を個別に調整することができ、例えば、使用する剤の種類、投与経路及び投与頻度を個別化することができる。或いは、療法は、標準的な治療過程を用いて、例えば、予め選択された剤並びに予め選択された投与経路及び投与頻度を用いて実施することができる。
以下に示す実施例は、本明細書において特許請求する化合物、組成物、物品、装置及び/又は方法をどのように作製及び評価するかについての完全な開示及び説明を提供するために提出するものであり、本発明を例示することのみを意図しており、本発明者らが自身の発明と認識する範囲を限定することを意図するものではない。数(例えば、量、温度等)に関する精度を確実にするように努めてきたが、ある程度の誤差及びずれは考慮すべきである。特段の指定がない限り、部は重量部であり、温度は℃単位であるか又は周囲温度であり、圧力は大気圧又は大気圧付近である。
a.一般合成手順
i.方法A:6−(4−(2−(4−シクロプロピル−3−フルオロフェニル)アセチル)ピペラジン−1−イル)ピリダジン−3−カルボニトリル
2−(4−シクロプロピル−3−フルオロフェニル)酢酸(150mg、0.772mmol)、4−(6−シアノピリダジン−3−イル)ピペラジン−1−イウムクロリド(218mg、0.850mmol、88%)及びHATU(382mg、1.0mmol)をDMF(3.0mL)中に含む混合物を冷却(氷)及び撹拌し、未希釈のDIPA(404μL、2.32mmol)を加えた。混合物を室温に加温して16時間撹拌した後、50℃で1時間加熱した。次いで混合物を室温に冷却し、水(10mL)で希釈し、酢酸エチル(2×15mL)で抽出した。抽出物を合一して1NのHCl水溶液、炭酸水素塩溶液及び飽和食塩水で洗浄し、Na2SO4で乾燥させ、濃縮した。残渣を25gのSiO2カートリッジ上で、ヘキサン中酢酸エチルのグラジエント(50%〜100%、及び100%)にかけることにより、標題化合物(160mg、56.7%)をベージュ色固体として得た。Rf=0.25(EtOAc)
2−(4−シクロプロピル−3−フルオロフェニル)酢酸(3.35g、17.2mmol)及び1−(6−シアノピリダジン−3−イル)ピペラジン−1,4−ジイウムクロリド(4.97g、19.0mmol)をDMF(35mL)中に含む混合物を冷却(氷)及び撹拌し、プロピルホスフィン酸無水物(13.3mL、22.4mmol)のDMF中50%溶液を添加した後、未希釈DIPA(13.8mL、79.3mmol)を加えた。反応混合物を室温までゆっくりと加温し、17時間撹拌した。次いで反応を水(100mL)でゆっくりと停止し(わずかに発熱)、10分間撹拌した後、ブフナー漏斗を用いて濾過し、水(500mL)で洗浄し、高真空下で乾燥させることにより、6−(4−(2−(4−シクロプロピル−3フルオロフェニル)アセチル)ピペラジン−1−イル)ピリダジン−3−カルボニトリル(5.95g、94.4%)をオフホワイト色固体として得た。この生成物の純度は95%を超えていた。生成物(4.77g)をMeOH−EtOAcの混合物(1:1、100mL)中に加えた。次いで懸濁液を80℃で10分間加熱することにより透明な淡黄色溶液を得た。溶液を濾過し、濾液を室温で24時間維持した。固体を濾過し、EtOAc(10mL)で洗浄し、乾燥させることにより、6−(4−(2−(4−シクロプロピル−3−フルオロフェニル)アセチル)ピペラジン−1−イル)ピリダジン−3−カルボニトリル(3.65g、76.5%)をオフホワイト色固体として得た。HPLC純度>99.9%。
i.実施例1:6−(4−(2−(4−シクロプロピル−3−フルオロフェニル)アセチル)ピペラジン−1−イル)ピリダジン−3−カルボニトリル
以下に示す表1の化合物を、本明細書に記載する方法と同一又は類似の方法で合成した。必要な出発物質は市販されているか、文献に記載されているか、又は有機合成の当業者により容易に合成される。
Claims (40)
- 式:
R3a、R3b及びR3cは、それぞれ独立に、水素、ハロゲン、C1〜C4アルコキシ及びC1〜C4アルキルから選択され、但し、R3a、R3b及びR3cの少なくとも1種はハロゲンであり;
R4は、水素、ハロゲン、−CN、SO2NH2、SO2CH3、SO2CF3及びNO2から選択される)で表される構造を有する化合物又はその医薬的に許容される塩。 - Q2は:
- Q2は:
- Q2は、構造:
- R3aはハロゲンである、請求項1に記載の化合物。
- R3aは−Fである、請求項1に記載の化合物。
- R3aはハロゲンであり、R3b及びR3cはそれぞれ水素である、請求項1に記載の化合物。
- R3aは−Fであり、R3b及びR3cはそれぞれ水素である、請求項1に記載の化合物。
- R3cはハロゲンである、請求項1に記載の化合物。
- R3cは−Fである、請求項1に記載の化合物。
- R3a及びR3cはそれぞれ−Fであり、R3bは水素である、請求項1に記載の化合物。
- R4は−CNである、請求項1に記載の化合物。
- R4は−Clである、請求項1に記載の化合物。
- 前記化合物は、構造:
- 前記化合物は:
- 前記化合物は:
から選択される、請求項1に記載の化合物。 - 式:
R4は、水素、ハロゲン、−CN、SO2NH2、SO2CH3、SO2CF3及びNO2から選択される)で表される構造を有する化合物又はその医薬的に許容される塩。 - R3aはハロゲンである、請求項0に記載の化合物。
- R3aは−Fである、請求項0に記載の化合物。
- R3aはハロゲンであり、R3b及びR3cはそれぞれ水素である、請求項0に記載の化合物。
- R3aは−Fであり、R3b及びR3cはそれぞれ水素である、請求項0に記載の化合物。
- R3cはハロゲンである、請求項0に記載の化合物。
- R3cは−Fである、請求項0に記載の化合物。
- R3a及びRcはそれぞれ−Fであり、R3bは水素である、請求項0に記載の化合物。
- R4は−CNである、請求項0に記載の化合物。
- R4は−Clである、請求項0に記載の化合物。
- 前記化合物は:
- 少なくとも1個の細胞のパントテン酸キナーゼ活性を調節する方法であって、少なくとも1個の細胞に、請求項1又は請求項0に記載の少なくとも1種の化合物又はその医薬的に許容される塩を有効量で接触させる工程を含む、方法。
- 調節は阻害である、請求項28に記載の方法。
- 前記細胞は、前記酵素パントテン酸キナーゼに関連する遺伝子の異型を特徴とする病態に関与する、請求項29に記載の方法。
- 前記細胞は、前記酵素パントテン酸キナーゼに関連する遺伝子の発現の誤調節を特徴とする病態に関与する、請求項29に記載の方法。
- 調節は活性化である、請求項28に記載の方法。
- 前記細胞は、前記酵素パントテン酸キナーゼに関連する遺伝子の異型を特徴とする病態に関与する、請求項32に記載の方法。
- 前記細胞は、前記酵素パントテン酸キナーゼに関連する遺伝子の発現の誤調節を特徴とする病態に関与する、請求項32に記載の方法。
- 対象のパントテン酸キナーゼ活性が関連する障害を治療する方法であって、前記対象に、請求項1又は請求項0に記載の少なくとも1種の化合物又はその医薬的に許容される塩を有効量で投与することを含む、方法。
- 前記対象に有効量のパントテネート及び/又はパントテン酸を投与することを更に含む、請求項35に記載の方法。
- パントテン酸キナーゼ活性が関連する前記障害は、高血糖を招く補酵素Aの誤調節及び/又は上昇が関連するものである、請求項35に記載の方法。
- パントテン酸キナーゼ活性が関連する前記障害は、神経変性を招くパントテン酸キナーゼ又は補酵素Aの欠乏が関連するものである、請求項35に記載の方法。
- 前記対象は、脳の鉄蓄積を伴う神経変性又はミトコンドリア機能の低下を特徴とする神経障害に罹患している、請求項35に記載の方法。
- パントテン酸キナーゼ活性が関連する前記障害は、ジストニア、錐体外路系作用(extrapyramidal effect)、嚥下障害、筋硬直及び/若しくは四肢硬直、舞踏アテトーゼ、振戦、認知症、痙性、筋力低下、又はてんかん発作から選択される、請求項35に記載の方法。
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